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Pulmonary Fibrosis
Researchers identify gene
linked to inherited form of fatal lung disease
DALLAS — Dec. 19, 2008 — Researchers at UT Southwestern
Medical Center have determined that a mutation in a gene
known for its role in defending the lungs against invading
pathogens is responsible for some inherited cases of a
lethal lung disease affecting older adults. The same
mutation may also be associated with lung cancer, the
researchers said.
This is the third gene that UT Southwestern scientists have
linked with idiopathic pulmonary fibrosis, or IPF. The study
appears online this week and in the January issue of
American Journal of Human Genetics.
In the U.S., about 200,000 patients have IPF, and about
40,000 patients die from the disease each year, according to
the Pulmonary Fibrosis Foundation. The disease typically
strikes people in their 50s and older, causing severe
scarring of the lungs. Death usually occurs within three
years of diagnosis.
Dr. Christine Garcia
(center) led researchers, including Dr. Philip Kuan
(left) and Dr. Yongyu Wang, in discovering that a
mutation in a gene known for its role in defending
the lungs against invading pathogens is responsible
for some inherited cases of a lethal lung disease
affecting older adults.
“We don’t have any medicines to treat this disease,” said
Dr. Christine Garcia, assistant professor in the Eugene
McDermott Center for Human Growth and Development and of
internal medicine at UT Southwestern and the study’s senior
author. “If a patient is younger than 65, lung
transplantation is an option, but most people who develop
IPF are older than that.”
The ultimate goal, Dr. Garcia said, is to find or develop a
medication that can stem the progression of this pulmonary
condition.
About one in 50 IPF patients have an inherited form of the
disease. It is this familial form of the disease that Dr.
Garcia her colleagues are focused on.
“We’ve been trying to identify the genes and genetic
variants that underlie this disease,” Dr. Garcia said. “Now,
we know there are multiple genes involved.”
In 2007, Dr. Garcia and her research team studied two large
families in which multiple individuals were affected with
IPF to search for a gene causing the disease. This led to
the discovery of mutations in genes called TERT and
TERC. These two genes are normally responsible for
producing the telomerase enzyme, which elongates the lengths
of DNA at the ends of chromosomes, called telomeres. In
normal cells, telomeres shorten each time the cell divides.
When they reach a certain length, the cell stops dividing.
In most cancerous cells, telomeres don’t shorten during cell
division, allowing the cells to remain effectively immortal.
Mutations in either of these two genes can be found in
almost 15 percent of those with familial IPF. Up to 40
percent have short telomere lengths and evidence of
telomerase dysfunction.
“But we were still left with a big question mark,” Dr.
Garcia said. “What about the rest of the families that have
normal telomere lengths? What was causing their lung
disease?”
In the current study, Dr. Garcia and her team focused on
families that did not have TERC or TERT
mutations. By using a genomic linkage approach — a technique
that scans the entire human genome for regions of DNA that
are shared in common by all the individuals with the disease
— they were led to mutations in a gene called SFTPA2.
The protein produced by this gene, surfactant protein A2, is
found in the fluid of the lungs and helps protect the organ
from invading pathogens.
Many of the individuals in this family who carried this
mutation had not only IPF but also lung cancer, especially
adenocarcinoma, with features of bronchioloalveolar cell
carcinoma. It is known that people with IPF have a higher
risk for developing lung cancer, and Dr. Garcia suspects
that mutations in the SFTPA2 gene are associated
with both IPF and lung cancer. Another family harboring a
different mutation in the SFTPA2 gene also had
members that exhibited IPF and lung cancer.
Dr. Garcia and her team are now working on molecular studies
in cells to determine why these gene mutations put patients
at risk for either of these diseases. They are also working
to develop an animal model in order to determine the
specific effects of SFTPA2 on different cells in
the lungs.
Other UT Southwestern researchers involved in the study were
lead author Dr. Yongyu Wang, a post doctoral researcher in
the McDermott Center; Dr. Philip Kuan, an internal medicine
resident;
Dr. Chao Xing, assistant professor of clinical sciences;
Jennifer Cronkhite, senior research associate in the
McDermott Center;
Dr. Fernando Torres, assistant professor of internal
medicine;
Dr. Randall Rosenblatt, professor of internal medicine;
Dr. Michael DiMaio, associate professor of
cardiovascular and thoracic surgery; Dr. Lisa Kinch,
a bioinformatics research scientist in biochemistry with the
Howard Hughes Medical Institute at UT Southwestern; and
Dr. Nick Grishin, associate professor of biochemistry
and an HHMI investigator.
The research was funded by the National Institutes of Health
and the Doris Duke Charitable Foundation.
How his illness inspired her
work, helped them bond
Chicago: September
9, 2008 - She is
Evel Knievel's
granddaughter and
Robbie Knievel's
daughter, which
makes Krysten
Knievel the heir to
not only the
legendary motorcycle
daredevil family
name but also
certain
expectations. And it
turns out, a girl
can't escape those
expectations just
because she grew up
hundreds of miles
away from both of
them, right here in
Chicago.
"People
automatically assume
that you're rich.
People automatically
assume that you're
crazy. They assume
that you jump things
with a motorcycle,"
Krysten tells me,
pausing to make sure
it's registering
that none of these
applies to her.
"They definitely
expect you to be
rich. That's for
sure."
I'm not sure what I
had expected, but
what I found was a
poised, ladylike
22-year-old working
on a social work
degree who didn't
seem at all crazy
and definitely not
rich, though she
won't rule out a
motorcycle jump,
which means I
probably ought to
reserve judgment on
crazy.
We were in a
sandwich shop on the
Far Northwest Side
near the modest home
of her mother and
stepfather, a
Chicago policeman.
She was squeezing in
the interview
between classes at
Northeastern
Illinois University
and her job as a
bartender/waitress
at a neighborhood
sports bar.
Running marathon to
raise money
When Evel Knievel
died last year at
69, I wrote about
how the once
world-famous showman
used to hang at a
Summit tavern when
he passed through
our area, giving the
patrons stories they
tell to this day. I
learned recently
that Knievel's
granddaughter was a
local girl and that
she was planning to
run the Chicago
Marathon next month
to raise money for
the Pulmonary
Fibrosis Foundation,
the lung disease
from which Knievel
suffered. She was
looking for
publicity. We agreed
to meet.
Krysten was born in
Phoenix, Ariz., and
was 3 years old when
her mother split
with Robbie, Evel's
equally accomplished
but not quite so
famous daredevil
son. Mom and
daughter moved in
with family members
in Oak Lawn. When
mom remarried,
Krysten came north
with her new family
and attended
Resurrection High
School.
One result was a
sometimes distant
relationship with
her dad, whom she'd
visit during
summers, and an
awkward one with her
grandfather. "He
kind of scared me,"
she said of "Grandpa
Evel." "If he liked
you, he was the
sweetest guy in the
world. If he didn't
like you, you knew
in two seconds."
Yet you get the
impression Krysten
wasn't sure where
she stood with him
until his later
years, when she got
involved with the
Pulmonary Fibrosis
Foundation, taking a
job there for a year
after high school as
events coordinator.
[You can learn more
or make a donation
at
www.pulmonaryfibrosis.org.]
Her interest helped
them bond.
Might as well jump?
"He talked to me
more. He said keep
calling. He told me
he was proud of me,
and he was proud of
my dad and he loved
my dad."
For the Knievel men,
long locked in a
father-son rivalry,
that was
significant.
"As showmen, they
were similar in some
instances, and they
were very
different," Krysten
explains. The
differences?
"My dad's choices in
involving himself
with drugs and
alcohol and handling
certain business
matters," says
Krysten, hesitantly
at first, for fear
of hurting his
feelings, then
making up her mind.
"I love my dad so
much. The truth is
the truth."
She'd actually
covered the same
ground on Robbie
Knievel's
short-lived reality
television series,
"Knievel's Wild
Ride," which aired
for seven episodes a
few years back.
Krysten appeared in
four of the
episodes, including
one titled "Daddy
Dearest," in which
she confronted him
about his drinking.
Krysten had hoped
her involvement with
the show would
jump-start a country
singing career. It
got her a short
stint in Los Angeles
with an indie label
that quickly folded
-- and a hard lesson
learned.
During summer visits
with her dad as a
child, Kristen would
occasionally
accompany him on
tour and go to his
jumps. She thought
it was cool to have
a father involved in
such an exciting
line of work.
"When I got older, I
realized it was more
of a curse. Part of
me wished I had a
dad with a normal
job who picked me up
from school and
carried a
briefcase."
So far, Krysten
hasn't inherited the
curse of jumping
motorcycles. When
visiting family
members in Montana,
she'll ride dirt
bikes and
four-wheelers,
"nothing crazy." She
said she has never
jumped anything
bigger than a small
dirt ramp in
somebody's back
yard. But she thinks
about it. She said
she's been
considering a "small
jump" that would be
a "quick way to make
some money."
"Not far," she says,
"A 50-foot gap.
Thirty feet.
Something that would
attract attention
but wouldn't kill
me."
So maybe she is a
little crazy.
Or maybe she just
inherited the
Knievel gene for
knowing how to get
attention.
Australian scientists develop potential
"blockbuster" drug
SYDNEY: Monday Aug 18, 2:10 PM (AFP) -
Australian researchers Monday said they had developed a drug
which could potentially spell an end to a life-threatening
condition caused by diabetes, heart disease and fibrotic
illnesses.
Scientists from the University of Melbourne and the city's St
Vincent's Hospital said the drug had been shown in animal trials
to prevent fibrosis, the build-up of irreversible scarring on
internal organs.
There are currently no treatments on the market for fibrosis
and the new drug, called FT-11, could be as important a
discovery as blood pressure drugs if effective, said Professor
Darren Kelly of the University of Melbourne.
"It would be an enormous blockbuster drug with an initial
market of around 2.0 billion dollars," he said.
Kelly said while the drug would not prevent diabetes -- a
chronic illness in which the body fails to produce enough of the
hormone insulin to process sugar -- it could prevent
complications such as kidney or heart disease.
"We are hoping to delay or prevent those complications which
would basically keep those patients off dialysis -- which would
have a huge benefit for their lifestyle," Kelly told AFP.
The drug, expected to be tested in clinical trials within 12
months, could be used to prevent diabetic kidney disease, heart
disease and potentially other health problems such as liver and
lung fibrosis, he said.
Speaking to the Australian Broadcasting Corporation, Kelly
said about 45 percent of diseases in the developed world could
be associated with some sort of pathological fibrosis.
"We know at the moment in rat studies that our compound
inhibited the development of fibrosis, and the interesting thing
in the future would be to see whether we can actually reverse
fibrosis," he said.
Agence France Presse.
Stem cells could lead to
better, safer drugs
June 16th, 2008:
Drug discovery is a cruel business. A hundred
thousand people die every year because of adverse drug side
effects. Millions die too young because drugs just aren't
good enough.
The problem is that scientists invent medicines to treat
people, but they have to use animal or tumor cells to do it.
Heart cells, brain cells and liver cells all die when you
try to keep them in a petri dish. So over decades
researchers have come up with jury-rigged tests. They use
preserved kidney cells extracted from a human fetus 30 years
ago to see if an experimental drug will disrupt the rhythm
of the heart. They use cells from a rat's digestive tract
with human receptors stuck in. They force huge doses of
every potential medicine down the throats of rodents. "The
system is failing," says Gabriela Cezar, who left
Pfizer to
study stem cells at the University of Wisconsin-Madison.
It's a testament to the ingenuity of pharmaceutical
researchers that the system works at all. Nine out of ten
drugs studied in humans turn out not to work or to be too
toxic. Sanofi-Aventis,
Pfizer and AstraZeneca
have all had promising compounds go up in flames because of
dangerous side effects. One solution may be to use embryonic
stem cells to test drugs for safety and efficacy. "You
should be able to get rid of some of the nasty drugs before
they even hit clinical trials," says uw-Madison stem cell
pioneer James Thomson. "And we're able to do that today."
Two years ago Thomson founded Cellular Dynamics
International, a biotech firm that uses embryonic stem cells
to make beating human heart cells, something that's never
before been available to drug companies. Thomson has avoided
the business world as long as possible but now says it is
time for his cells to go commercial. Roche
is the first announced customer. Earlier this year it began
tests with Thomson's heart cells to catch cancer drugs that
are toxic to the heart. A rival company, Sweden's Cellartis,
is developing ways to test drugs for liver toxicity (with
AstraZeneca) and for birth defects (Pfizer).
Even bigger, but further off, is the potential that being
able to study neurons in a dish will allow researchers to
understand what causes Parkinson's or Lou Gehrig's disease.
It could be that in 20 years almost every medical researcher
is going to use embryonic stem cells as basic tools. "That
is going to profoundly change medicine," says Thomson.
Catapulting this work forward is the discovery of ways to
create cells that act like embryonic stem cells but without
ever using embryos. Last year Japan's Shinya Yamanaka and
Thomson simultaneously showed that adult human cells could
be transformed into embryolike stem cells by activating only
four genes using viruses. "That has galvanized the field,"
says Alexander Rod MacKenzie, head of basic research at
Pfizer.
University of California, San Diego researcher Lawrence
Goldstein is using these so-called induced pluripotent stem
cells to make neurons that are "genetically identical" to
those of Alzheimer's patients. He is collecting 50 skin
samples from Alzheimer's patients in order to hunt for new
drugs.
Wisconsin's Cezar has started a biotech called Stemina
that is using stem cells to get to the roots of autism.
Autism appears in a tenth of the children born to mothers
who take the epilepsy drug valproate. Valproate is known to
injure neurons, so Cezar is converting embryonic stem cells
into live neurons and adding valproate to the sample. The
neurons gush chemicals that she is comparing to those found
in brain cells of people with autism. If there's a match,
Cezar could be on a path toward diagnostic tests or drugs.
Stemina is using a similar strategy for a range of potential
drugs. "[Autism] is an epidemic," she says, "and we have no
idea about the cause.
Medical Technology Fixing Pharma Robert Langreth and Matthew
Herper
Biomarkers identified for idiopathic
pulmonary fibrosis
The first evidence of a distinctive protein
signature that could help to transform the diagnosis
and improve the monitoring of the devastating lung
disease idiopathic pulmonary fibrosis (IPF) is being
reported by University of Pittsburgh School of
Medicine researchers in this month’s edition of
PLoS Medicine, an open-access journal of the
Public Library of Science.
In the paper, Naftali Kaminski, M.D.,
director of the Dorothy P. & Richard P. Simmons
Center for Interstitial Lung Disease in the Division
of Pulmonary, Allergy and Critical Medicine at the
University of Pittsburgh School of Medicine, and his
colleagues describe a unique combination of blood
proteins that appears to distinguish IPF patients
from normal controls with extraordinary sensitivity
and precision.
“Our findings suggest that we may be able to monitor
what is happening in the lungs by measuring certain
proteins in the peripheral blood,” explains senior
author Dr. Kaminski, who also is associate professor
of medicine. “More study is needed to confirm
whether these biomarkers might be useful as a
clinical blood test to detect lung fibrosis. But
right now, there is no straightforward test for IPF.
The lung is not highly accessible; biopsy procedures
carry risk, and while imaging is good, it can’t
follow the disease biologically.”
IPF is a degenerative illness distinguished by
progressive lung scarring and diminished breathing
capacity, typically leading to death within about
five years of diagnosis. It is estimated that 5
million people worldwide and 130,000 in the United
States are affected by pulmonary fibrosis and about
30,000 people die of the disease every year. For
this study, researchers analyzed the concentrations
of 49 proteins in the plasma of 74 patients with IPF
and 53 normal controls. A combination of five
proteins related to normal tissue breakdown and
remodeling and certain disease processes, including
arthritis and cancer, was found to be highly
indicative of IPF.
Increases in two of the five, matrix
metalloproteinases (MMP) 7 and 1, also were observed
in tissue and fluid taken from the lungs of IPF
patients. Other proteins in the IPF signature are
matrix metalloproteinase 8, insulin-like growth
factor binding protein 1 and tumor necrosis factor
receptor superfamily member 1A. “These proteins were
increased in IPF patients, but not in patients with
lung illnesses such as chronic obstructive pulmonary
disease,” says Ivan O. Rosas, M.D., first author on
the study and assistant professor of medicine,
University of Pittsburgh School of Medicine.
Elevated MMP1 and MMP7 also distinguished IPF when
compared to levels associated with another disease
that closely mimics IPF, called subacute/chronic
hypersensitivity pneumonia. In particular, increased
concentrations of MMP7 “may be indicative of
asymptomatic lung disease and perhaps reflect
disease progression,” Dr. Rosas says.
“One of the challenges is to know whether a blood
protein actually reflects the situation in the
lung,” notes Thomas J. Richards, Ph.D., study
co-first author and research assistant professor in
the Division of Pulmonary, Allergy and Critical Care
Medicine, University of Pittsburgh School of
Medicine. The team evaluated all the genes expressed
in IPF-affected lung tissue to determine the
proteins in the peripheral blood on which they
should focus. Based on their detailed analysis, the
team believes that increased levels of these five
proteins probably are reflective of the disease.
“IPF can have a slow progression, so drug companies
may wait a long time to see whether a particular
drug is having any effect,” says Dr. Kaminski. “But
a blood biomarker could indicate whether a drug is
working earlier. The biomarkers also might be used
for risk assessment and for evaluation of disease
progression.”
Some known causes of pulmonary fibrosis include
occupational and environmental exposure to asbestos,
metal dust, farming chemicals and mold, an
inflammatory disease called sarcoidosis, radiation,
drug reactions, autoimmune disorders and possibly a
genetic predisposition, according to the American
Lung Association. Most cases are considered to be
idiopathic, or of unknown origin. There is no proven
effective therapy for IPF, and most drug
interventions are considered experimental. Long-term
benefit may be possible with lung transplantation, a
radical approach dependent upon a limited number of
donated organs.
Source: University of Pittsburgh,
April 29, 2008
Growth factors in idiopathic
pulmonary fibrosis:
relative roles
Introduction
Idiopathic pulmonary fibrosis (IPF) is clinically a
restrictive lung disease that characteristically progresses
relentlessly to death from respiratory failure. Median
survival of newly diagnosed patients with IPF is about 3
years, similar to that of clinical stage 1b non-small cell
lung cancer. The quality of life for IPF patients is also
poor. Despite this, there has been remarkably little
progress in development and/or assessment of therapeutic
strategies for IPF.
High dose corticosteroids alone or in combination with
other immunosuppressive agents continue to be prescribed,
although there is no clinical evidence of their efficacy.
Recent data indicate that, following such treatment, less
than 30% of IPF patients show objective evidence of
improvement, including better survival, while there is a
high incidence of drug-related adverse effects. Furthermore,
it remains unclear whether a positive response can be
attributed to the treatment itself or to the patients having
a less aggressive form of the disease. For significant
improvements to occur in the survival of patients with IPF,
there needs to be development of novel and more precisely
targeted therapies. Selection of future appropriate regimes
must be critically dependent on improved characterization of
the molecular pathways driving pathogenesis of IPF.
The focus of research efforts in a number of
laboratories, including our own, has thus been directed
towards establishing the relative roles of molecules that
may determine the outcome of associated profibrogenic
processes. Accordingly, such efforts could lead to potential
candidate molecules being exploited for therapeutic
manipulation. Support for this strategy is echoed in the
recent consensus statement issued jointly by the American
Thoracic Society and the European Respiratory Society, in
which the roles of "various cytokines and growth factors"
are described as "critical" to the process of fibrosis.
Growth factors: multiple profibrogenic
functions
Individual growth factors involved in the development of
pulmonary fibrosis invariably regulate other cell functions,
as well as cell proliferation. They may originate from a
variety of sources including immune cells, endothelial
cells, epithelial cells, fibroblasts, platelets and smooth
muscle cells. However, in the context of IPF pathogenesis,
it is now suggested that IPF is an 'epithelial-fibroblastic
disease' (see Pathogenesis of IPF: new concepts – is
inflammation relevant?). It is therefore the interactions of
growth factors with these epithelial and fibroblast cell
types that are most critical in determining whether the
ultimate outcome of wound-healing responses to lung injury
is IPF.
Growth factors have predominantly been described in
fibroblasts, which are recognised key players in wound
healing. It is becoming increasingly apparent, however, that
'injured' and 'activated' alveolar epithelial cells (AECs)
both secrete and respond to growth factors themselves,
particularly in IPF, thereby contributing to the outcome of
the profibrogenic processes. Functions regulated in
fibroblasts that directly influence fibrogenesis include
enhancing or inhibiting extracellular matrix (ECM) protein
synthesis, chemotaxis, production of metalloproteinases and
their inhibitors, expression of adhesion molecules, and
angiogenesis. Much less is known about how growth factors
regulate AEC function to modulate fibrogenesis but, in AECs
obtained from IPF patients, growth factors are potentially
responsible for secretion of metalloproteinases and,
paradoxically, inhibit proliferation through enhancement of
apoptosis.
It also seems probable from familial studies that there
is a genetic predisposition to development of IPF. Although
the nature of any genetic component is at present unknown,
polymorphic genes for a number of fibrogenic growth factors
have been found. Cellular phenotype may thus be an important
determinant of growth factor response and, hence, of
increased susceptibility to development of IPF.
This review focuses on those growth factors for which
there is compelling data for their involvement in the
molecular pathways controlling fibrogenesis. Within the
constraints of this forum, it will not be possible to fully
consider all aspects of this involvement. Intentionally, we
will update, rather than simply repeat, what is already
widely known regarding these mediators. We specifically
highlight new important findings, with implications for
novel targeted therapeutic approaches in IPF.
Pathogenesis of IPF: new concepts – is
inflammation relevant?
Recent developments strongly challenge the current
concept of IPF pathogenesis. The widely held view has been
that the distinct histopathological subsets of IPF (usual
interstitial pneumonia [UIP], desquamative interstitial
pneumonia, non-specific interstitial pneumonia, and acute
interstitial pneumonia) share common pathogenetic features,
regardless of the initiating agent (where known).
A hypothesis of persistent interstitial inflammation
leading to, and modulating development of, fibrosis has
therefore developed. Underpinning this hypothesis are many
studies that have highlighted the critical importance, in
determining the outcome of pathogenic events, of polypeptide
mediators released both from resident and immune cells.
Indeed, this paradigm appears to be sustained in a number of
potentially fibrotic lung diseases that have a prominent
inflammatory process during their early stages and that
exhibit a favorable response to steroid-based
anti-inflammatory therapies, particularly if therapy begins
during the inflammatory phase (e.g. desquamative
interstitial pneumonia, non-specific interstitial pneumonia,
hypersensitivity pneumonitis, and sarcoidosis).
Recent investigations, however, have shown that
consideration of the constituent histological patterns of
IPF as separate pathological entities correlates much better
with clinical outcome, those with UIP tending to have the
worst prognosis. Anti-inflammatory therapies, even in
combination with potent immunosuppressives, fail to improve
the disease outcome. Such a distinction in clinical course
has led to a redefinition of IPF diagnostic criteria by the
American Thoracic Society and the European Respiratory
Society, and a requirement for the histopathological
presence of UIP. Furthermore, there is very little evidence
to support the presence of any prominent inflammation in the
early stages of UIP. In fact, inflammation appears not to be
required for the development of the fibrotic response, which
may account for the observed therapeutic failures.
The documented inflammation found in UIP is usually mild,
and is associated with areas of ongoing fibrosis rather than
prefibrotic alveolar septa. Selman et al. have
advanced a new hypothesis in which they propose that UIP
(IPF) represents a model of abnormal wound healing,
resulting from multiple, microscopic sites of ongoing AEC
injury and activation, with release of fibrogenic mediators.
These mediators lead to areas of fibroblast-myofibroblast
foci (sites of injury and abnormal repair characterised by
fibroblast-myofibroblast migration and proliferation), to
decreased myofibroblast apoptosis, and to enhanced release
of, and response to, fibrogenic growth factors. These foci
evolve and coalesce into more widespread fibrosis.
Abnormal wound-healing model of idiopathic
pulmonary fibrosis pathogenesis. In the model
proposed by Selman et al., microinjuries
damage the epithelium and cause the release of
profibrogenic growth factors and the development of
an antifibrinolytic microenvironment that promotes
wound clot formation. Proliferating and
differentiating fibroblasts migrate through a
disrupted basement membrane, secreting extracellular
matrix (ECM) proteins and angiogenic factors. An
imbalance in matrix-degrading and matrix-enhancing
enzymes favours increased deposition of ECM.
Myofibroblasts are not removed and they release
growth factors that promote epithelial cell
apoptosis.
Associated with abnormal repair are aberrant processes of
re-epithelialisation and ECM remodelling, leading to
basement membrane disruption, angiogenesis, and fibrosis.
Following injury, rapid re-epithelialisation is essential to
restoration of barrier integrity and requires epithelial
cell migration, proliferation and differentiation of type II
AECs into type I AECs. In IPF, the ability of type II AECs
to carry out this migration, proliferation and
differentiation appears seriously compromised. A number of
profibrogenic mediators seem to be implicated in this
deficiency. Impairment of this normal wound-healing response
could occur through the observed excessive loss of AECs by
apoptosis that seems to be a feature of IPF. In parallel,
proliferating fibroblasts emerging during the normal repair
process are able to self-regulate their production of matrix
synthesis and degradation components and mitogens, through
autocrine mechanisms that, in established fibrosis, may be
dysregulated in increased numbers of cells displaying an
altered profibrotic myofibroblast-like phenotype.
Growth factors implicated in IPF
pathogenesis
Growth factor production from damaged
AECs
It is now readily apparent that the injured epithelium in
IPF, in close proximity to the interstitial fibroblasts,
elaborates a number of key growth factors. This not only
allows for autocrine control of epithelial cell growth and
differentiation, but also enables paracrine control of
fibroblast proliferation, chemotaxis and ECM deposition to
occur. The expression of several key fibrogenic growth
factors has been highlighted and can be localised
predominantly to hyperplastic type II AECs.
Tumour necrosis factor-alpha
The consequences of tumour necrosis factor-alpha (TNF-α)
overexpression or deficiency have been explored in animal
models of fibrosis. For example, mice overexpressing TNF-α
develop IPF-like fibrosis, whereas TNF-α-deficient
or double TNF-α receptor
knockout mice show resistance to bleomycin-induced fibrosis
(for a review, see. Furthermore, a TNF-α
promoter polymorphism seems to confer increased risk of
developing IPF.
It has been shown that type II AECs are a primary source
of TNF-α in the lung. In human
IPF, compared with cells from normal lungs, TNF-α
immunoreactivity is increased in hyperplastic TNF-α
type II AECs [. In the context of the proposed abnormal
wound-healing model of IPF, TNF-α
release from damaged AECs could thus exert profound
profibrotic effects.
TNF-α may increase fibroblast
proliferation, differentiation and collagen transcription
indirectly via transforming growth factor-beta (TGF-β)
or platelet-derived growth factor (PDGF) induction pathways
. Furthermore, TNF-α activity
promotes induction of matrix-degrading gelatinases that can
enhance basement membrane disruption and can facilitate
fibroblast migration. Finally, promising results have been
obtained by treating IPF patients with pirfenidone, a novel
antifibrotic agent with anti-TNF-α
properties .
Platelet-derived growth factor
Many studies have shown that PDGF is a potent fibroblast
mitogen and chemoattractant. There is in vitro
evidence suggesting that a number of fibrogenic mediators
including TNF-α, TGF-β,
IL-1, basic fibroblast growth factor and thrombin may
exhibit PDGF-dependent profibrotic activities.
PDGF comprises two polypeptide chains, A and B, and is
active as either of the homodimers or as a heterodimer.
Activation of α and
β PDGF-receptor (PDGF-R)
subunits, which have different affinities for the A and B
isoforms, occurs with their dimerisation. In normal adult
lung, PDGF and PDGF-R are expressed at low levels in
alveolar macrophages, but they are upregulated in IPF.
Additionally, in early-stage but not late-stage IPF, type II
AECs and mesothelial cells express PDGF and PDGF-R. In
particular, the type II AECs in early-stage IPF strongly
expressed mRNA for PDGF-B and PDGF-Rβ
[. Expression of PDGF-B from an adenoviral vector or
administration of recombinant human PDGF-BB, delivered
intratracheally into rat lungs, produces histopathologic
features of fibrosis, further supporting a role for PDGF in
IPF fibrogenesis. Moreover, suppression of PDGF peptide
synthesis by the antifibrotic agent pirfenidone is
associated with inhibition of bleomycin-induced pulmonary
fibrosis in the hamster. Whether PDGF is essential for
development of fibrosis, however, will only be known
following experiments with recently developed PDGF-R
knockout chimeras.
Transforming growth factor-beta
The TGF-β family of peptides
has similar biological functions and binds to the same
receptors. It is only TGF-β1,
however, that is consistently found to be upregulated at
sites of fibrogenesis. TGF-β1 is
a fibroblast chemoattractant and is able to exert a bimodal
effect on fibroblast proliferation, via an autocrine
PDGF-dependent pathway. Moreover, it is also the most potent
stimulator of fibroblast collagen production yet described.
This enhanced collagen deposition is mediated through
increased mRNA transcription and stability, through
decreased degradation of procollagen via inhibition of
collagenase production, and through increased production of
matrix metalloproteinase inhibitors (including tissue
inhibitor of metalloproteinase, plasminogen activator
inhibitor and α-macroglobulin.
Immunohistochemical studies in patients with IPF reveal
enhanced expression of TGF-β1 in
a number of cell types. In early disease with minimal
fibrosis, this was found primarily in alveolar macrophages.
In advanced honeycomb fibrotic lesions typical of a UIP
phenotype, however, TGF-β1
overexpression was localised in hyperplastic type II AECs. A
large number of studies with animal models of pulmonary
fibrosis have confirmed the fibrogenic nature of TGF-β1
overexpression and have demonstrated the antifibrotic
effects of TGF-β1 inhibition,
such as with anti-TGF-β1
antibodies. Furthermore, a polymorphism at position +915 in
the signal sequence of the TGF-β1
gene confers an amino acid change with effects on TGF-β1
production. The 'high-producer' allele is associated with
allograft fibrosis and pre-transplant fibrotic pathology in
patients requiring lung transplant. Unfortunately, however,
the pluripotent nature of TGF-β1
activity in the lung has prevented the use of such specific
anti-TGF-β1-directed therapies.
Therapeutic efforts are now focusing on modulators of
TGF-β1 activity such as
pirfenidone, which inhibits TGF-β1
gene expression in vivo, inhibits TGF-β1-mediated
collagen synthesis and fibroblast mitogenesis in vitro,
and appears to slow progression of IPF when administered to
patients.
Insulin-like growth factor-1 and
insulin-like growth factor-binding proteins
Insulin-like growth factor-1 (IGF-1) stimulates
proliferation of a variety of mesenchymal cell types,
including fibroblasts where it may act synergistically with
other fibrogenic growth factors, and is also a potent
inducer of collagen synthesis. IGF-1 regulation is complex,
with alternative mRNA splicing leading to the expression of
a number of IGF-1 variants and post-translational control of
IGF-1 activity by at least six high-affinity insulin-like
growth factor-binding proteins (IGFBPs).
IGF-1 activity was first identified in alveolar
macrophages (AM)from IPF patients. Paradoxically, however,
recent data from our laboratories show total IGF-1
expression actually decreases in unfractionated
bronchoalveolar lavage cells (BALC) from IPF patients,
compared with normal controls. This correlates with findings
of high levels of IGF-1 and IGF-1 receptor expression only
in early-stage IPF with minimal fibrosis, localised to a
number of cell types including AM, and prominantly in type
II AECs. In late-stage IPF or normal controls, only AM
continued to express these molecules. These data point
towards the importance of IGF-1 expression in the initiation
of IPF. Furthermore, primary human airway epithelial cells
produce IGF-1 in vitro, and the IGF-1 component of
their conditioned media accounts for most of the mitogenic
activity of the conditioned media for lung fibroblasts.
IGF-1 activity is regulated by the presence of IGFBPs,
able to both stimulate and inhibit IGF-1-mediated actions
and to exert IGF-independent effects themselves. IGFBP-3 and
IGFBP-2 levels are increased in IPF bronchoalveolar lavage
fluid and in type II AECs exposed to oxidant injury.
Furthermore, in type II AECs, these increases are associated
with induction of apoptosis and show distinct patterns of
distribution, with IGFBP-3 most abundant in the
extracellular compartment and IGFBP-2 mainly intracellular,
but with significant nuclear localisation. In primary human
lung fibroblasts, data from our laboratories show potent
induction of IGFBP-3 by fibrogenic TGF-β1.
Taken together these findings support IGF-independent
functions for IGFBP-3 and IGFBP-2 in fibrogenesis,
putatively involving transcriptional activation of
growth-regulating genes and regulation of apoptosis.
Interleukin-4
Human fibroblasts demonstrate enhanced proliferation and
collagen synthesis, with a simultaneous downregulation of
IFN-γ transcription, in response
to IL-4. This loss of antifibrotic activity of IFN-γ
may promote a pro-fibrotic mediator imbalance and favour
selection of a type 2 immune response. Indeed, evidence
shows that IPF patients have a predominantly type 2 (T-cell
helper [Th]2-like mediator) immune response. Furthermore,
patients having drug-responsive forms of interstitial lung
disease (sarcoid and extrinsic allergic alveolitis)
demonstrate upregulation of both IFN-γ
and IL-4 expression on type II AECs, whereas IPF patients
fail to express IFN-γ, perhaps
because of a predisposing IFN-γ
microsatellite polymorphism. Simultaneous promotion of a Th2
(IL-4-led) response and suppression of the Th1 (IFN-γ-led)
response could thus promote fibrogenesis through enhanced
and unchecked IL-4 (Th2) expression.
Endothelin-1
Endothelin-1 (ET-1) is a peptide of diverse function
implicated in the development of a number of diseases,
including IPF, where it may promote fibroblast and AEC
proliferation, fibroblast differentiation into
myofibroblasts, chemotaxis, contraction, and collagen
synthesis while inhibiting collagen degradation. ET-1 is
able to induce a number of fibrogenic growth factors through
paracrine stimulation of different cell types, including
TNF-α, TGF-β
and fibronectin, and may enhance neovascularisation through
induction of vascular endothelial growth factor (VEGF). ET-1
is converted from an inactive form, big endothelin, to
mature endothelin by endothelin-converting enzyme-1 (ECE-1).
In IPF lungs, big endothelin, ECE-1 and ET-1 expression is
enhanced and co-localised, particularly in airway epithelial
cells and type II AECs, and correlates with disease
activity. ET-1 effects are mediated through ET-A and ET-B
receptors, and ET-1 receptor antagonists such as bosentan,
which blocks both receptors, have been used with partial
success to inhibit fibrosis in a rat model of
bleomycin-induced pulmonary fibrosis.
Connective tissue growth factor
Connective tissue growth factor (CTGF) is an
immediate-early gene (ccn2) product, a member of the
structurally related CCN family of proteins. CCN members
exhibit a wide range of functions but, in general, are
secreted proteins associated with the ECM that regulate
biological processes such as adhesion, angiogenesis and
fibrosis. CTGF is a potent enhancer of fibroblast
proliferation, chemotaxis and ECM deposition.
In mesenchymal cell types, CTGF induction is primarily
but not exclusively mediated by TGF-β,
through a TGF-β-response element
in the CTGF promoter. There has thus been considerable
interest in CTGF as a downstream mediator of TGF-β
actions, not least because CTGF may account for many of the
profibrogenic activities attributed to TGF-β
and may be a more suitable target for antifibrotic
therapies.
Many recent studies have shown increased expression of
CTGF to be associated with fibroproliferative disorders, and
we recently reported this in IPF. There appear to be
multiple cellular sources of CTGF in the lung, including
fibroblasts and bronchial epithelial cells. Downregulation
of CTGF expression seems to offer protection from fibrosis.
A preliminary trial of IFN-γ
co-therapy in IPF patients led to clinical improvement,
associated with inhibition of CTGF gene expression.
Overexpression of TGF-β1 in mice
by delivery of a TGF-β1
adenovirus vector results in pulmonary fibrosis, but in
Smad3 knockout mice there is resistance to development of
fibrosis associated with a failure to activate CTGF gene
expression. Furthermore, we recently found that Simvastatin,
an HMG-CoA reductase inhibitor with described antifibrotic
properties, also inhibits CTGF expression in isolated IPF
patient-derived lung fibroblasts (K Watts, E Parker, MA
Spiteri, JT Allen, unpublished data, 2001).
Emergence and persistence of
myofibroblasts
The emergence of altered fibroblast phenotypes during
tissue remodelling is well recognised. Myofibroblasts,
differentiated fibroblasts with morphological features of
smooth muscle cells, are a feature of fibrotic lesions and
comprise the main cell type of the fibroblast foci already
described. Functionally they seem to be involved in ECM
production and the process of tissue contraction, necessary
for wound healing.
Fibroblasts isolated from IPF patients are
characteristically more myofibroblast like than those from
normal subjects, as determined from α-smooth
muscle actin expression. Recent data from a co-culture model
of wound healing indicates that TGF-β1
induces, whereas IL-1β inhibits,
fibroblast differentiation into a myofibroblast phenotype
following epithelial cell injury. Activators of TGF-β1,
such as fibroblast-derived thrombospondin-1, are necessary
to convert latent TGF-β1 into
its active form at the fibroblast surface to facilitate this
differentiation. The myofibroblasts show abnormal responses
to, or release of, growth factors, other mediators and ECM
proteins (including enhanced collagen, TGF-β1,
matrix metalloproteinase-9 and tissue inhibitor of
metalloproteinase expression), giving them a profibrotic
secretory phenotype. A consequence of the sustained presence
of TGF-β1 is an inhibition of
(IL-1β-induced) myofibroblast
apoptosis. This inhibition prevents the necessary rapid
clearance of these cells by apoptosis that is required for
normal cessation of repair, and results in continued,
deleterious ECM production.
Other growth factors with apoptosis-modulating properties
could also be involved; in particular CTGF, which acts
downstream of TGF-β. Using CTGF
antisense oligonucleotides to inhibit CTGF-mediated actions
on apoptosis, we found a contrast between CTGF-induced
apoptosis of primary bronchial epithelial cells and
CTGF-inhibited apoptosis of primary IPF-derived lung
myofibroblasts (JT Allen, unpublished data, 2001). These
data suggest that CTGF could contribute to the persistence
of myofibroblasts in the fibrotic lung, but whether CTGF can
directly induce a myofibroblast phenotype itself is as yet
unknown.
Interestingly, an IPF-derived primary myofibroblast-like
cell line demonstrates enhanced responsiveness to TGF-β1,
compared with normal fibroblasts. This results in enhanced
expression of both IGF-1 and CTGF, perhaps involving a
fibroblast subpopulation overexpressing TGF-β
type I and type II receptors. IGF-1 inhibition of apoptosis
is well recognised and its increased expression in these
cells may therefore contribute to the putative inhibition of
myofi-broblast apoptosis.
Finally, myofibroblasts from IPF also appear to be
deficient in their production of eicosanoid autocrine
inhibitors of proliferation and ECM deposition, apparently
through their inability to upregulate cyclooxygenase-2 and
TNF-α receptor, necessary for
enhanced prostaglandin E2 (PGE2)
synthesis. Both TNF-α and PGE2
have been shown to reduce expression of CTGF, providing an
endogenous mechanism for terminating the CTGF response to
TGF-β1 and resulting in
resolution of the fibroproliferative response without
progression to fibrosis. Downregulation of myofibroblasts by
induction of apoptosis (e.g. using Simvastatin) or by
inhibiting their differentiation (e.g. using IFN-γ)
have thus been suggested as potential novel therapeutic
approaches. However, in reducing myofibroblast
proliferation, care needs to be taken to avoid a parallel
reduction in AEC proliferation, which would inhibit
re-epithelialisation. In this regard, data for CTGF
antisense is encouraging (see earlier in this section),
showing both a reduction of epithelial apoptosis and an
enhancement of fibroblast apoptosis. Taken together, these
data support the development of CTGF-targeted therapies for
IPF.
Failure of endogenous regulation of wound-healing
in idiopathic pulmonary fibrosis (IPF). Injuries to
alveolar epithelial cells (AECs) result in
upregulation of growth factor production, including
tumour necrosis factor-alpha (TNF-α).
Binding of TNF-α to TNF-α
receptor (TNF-αR)
activates the cyclooxygenase-2 (COX-2) pathway and
induces synthesis of prostaglandins including
prostaglandin E2 (PGE2) and
6-keto-prostaglandin F1α
(PGF1α).
Prostaglandins exert negative feedback control of
AEC TNF-α expression and
autocrine inhibition, through raised intracellular
cAMP levels, of the connective tissue growth factor
(CTGF) response to transforming growth factor-β.
This results in limited and healthy wound healing,
and prevents further progression to fibrosis. In
IPF, however, myofibroblasts exhibit marked
deficiencies in TNF-α
receptor expression and COX-2 induction that result
in reduced synthesis of prostaglandins, and a
failure in the normal self-limiting wound-healing
response (broken arrows), ultimately leading to
fibrosis. PRs, prostaglandin receptors.
Growth factor-mediated AEC apoptosis
Timely re-epithelialisation following lung injury is
crucial to the successful outcome of the wound-healing
process, and recent evidence suggests that dysregulation of
apoptosis may occur, perhaps involving the Fas pathway.
Fibrogenic growth factors such as TNF-α
and TGF-β upregulate
pro-apoptotic co-factors (e.g. p53, p21(Waf1/Cip1/Sid1)
and bax) required for Fas-dependent cell death, and these
are enhanced in hyperplastic AECs from IPF. TGF-β1
also induces lung epithelial cell apoptosis through
receptor-activated Smad signalling.
Although there is some evidence that early loss of
epithelial cells can occur by Fas-mediated apoptosis, it is
unclear from studies in an animal model of bleomycin-induced
pulmonary fibrosis and IPF whether this is a prerequisite
for the development of fibrosis. In a series of studies,
Uhal and colleagues revealed that, in IPF fibrotic lesions,
AECs exhibit enhanced apoptosis. It also seems that adjacent
myofibroblasts release apoptotic peptides, angiotensinogen
and its derivative, the fibroblast mitogen angiotensin II,
that can induce this AEC apoptosis through angiotensin II
receptor activation pathways.
As might be expected, approaches that try to enhance AEC
proliferation and thus promote repair have been advocated as
possible novel therapies for IPF. Inhibitors of
apoptosis-effector caspases can effectively prevent
epithelial cell apoptosis and fibrosis in the murine
bleomycin model. Captopril, an angiotensin-converting enzyme
inhibitor, has the useful
in vitro properties of inhibiting Fas-mediated
epithelial cell apoptosis and inducing fibroblast apoptosis,
and is currently undergoing clinical trials in Mexico.
However, preliminary results do not show any additional
improvement over combination therapy with inhaled steroid
and colchicine. Keratinocyte growth factor, a mitogen and
differentiation growth factor for type II AECs, has been
found to have a protective effect against development of
fibrosis in animal models of bleomycin-induced pulmonary
fibrosis, where it downregulates TGF-β
and PDGF-BB expression. Similarly, hepatocyte growth factor
stimulates proliferation, migration and fibrinolytic
capacity in A549 AECs and attenuates collagen deposition in
a murine bleomycin-induced pulmonary fibrosis model. Of
note, the antifibrotic effects of hepatocyte growth factor
were maintained even when administered after development of
the fibrosis.
Growth factor-mediated angiogenesis
Neovascularisation in the lungs of IPF patients was first
identified by morphological examination, but there have been
few studies to characterise its role in the fibrogenic
process. Vessel formation requires endothelial cell
migration, proliferation and degradation of ECM, thought to
be regulated by a number of growth factors, and its
initiation is dependent on the balance between angiogenic
and angiostatic factors.
Members of the CXC chemokine family can exert opposing
effects on angiogenesis due to the presence or absence of
three amino acids (Glu-Leu-Arg; the ELR motif). IL-8
(containing the ELR motif) is thus angiogenic, while
interferon-inducing protein-10 (IP-10) (lacking the ELR
motif) is angiostatic. Levels of IL-8 are increased and
those of IP-10 decreased in IPF samples compared with
controls, favouring net angiogenesis. Furthermore, depletion
of IL-8 or IP-10 from IPF fibroblast-conditioned media
decreases or increases angiogenesis, respectively, and IP-10
administered to mice reduces the fibrotic response to
bleomycin, through regulation of angiogenesis.
VEGF is an established, essential, angiogenic factor. In
a rat model of bleomycin-induced pulmonary fibrosis,
increased numbers of VEGF-positive type II AECs and
myofibroblasts were identified localised in fibrotic
lesions. Recent data have shown that VEGF induces expression
of CTGF, apparently through TGF-β-independent
pathways, which is mediated through VEGF receptors Flt1 and
KDR/Flk1. CTGF itself is angiogenic, inducing endothelial
chemotaxis and proliferation and neovascularisation in
vivo, mediated via binding to integrin
αvβ3.
Furthermore, CTGF antisense inhibits both proliferation and
migration of vascular endothelial cells in vitro.
It is as yet unclear whether CTGF contributes to the
observed neovascularisation in IPF, and whether VEGF
regulation of CTGF provides an alternative pathway for CTGF
overexpression in IPF lungs.
Conclusion
Considerable progress has been made in recent years
towards our understanding of the pathogenesis of IPF. The
critical role of a number of interacting growth factors in
the initiation and maintenance of fibrogenesis has been
highlighted. However, clinical progress to an effective
therapy for IPF has not been achieved, in spite of promising
results from novel antifibrotic therapies in animal models.
This suggests that more targeted approaches must be
developed, while at the same time more caution should be
exerted in extrapolating data from animal studies to human
IPF. The key must lie in dissecting the crucial, intricate
molecular mechanisms that control fibrogenesis.
Recent findings point to possible genetic predisposition
and the interactions of a limited number of key growth
factors with pathways regulating processes such as apoptosis
in AECs and myofibroblasts. Since it appears probable that
only a few of these pathways are crucial in IPF, precise
targeting of any one of these pathways, via single or
several growth factors, could yield potential benefits. By
directing future studies toward dissecting the regulatory
pathways of growth factor expression in these cells, we can
thus develop subtle approaches for targeting the processes
they control and therefore attempt to halt the downward
clinical progression of human IPF.
Potential growth factor-mediated antifibrotic
strategies. A universal cell (fibroblast, epithelial
cell or inflammatory cell) is depicted with growth
factor-processing pathways highlighted (solid
arrows). Growth factors may exert autocrine and/or
paracrine effects. In idiopathic pulmonary fibrosis,
growth factor functions may be diminished or
enhanced and reversing these effects could offer
potential therapeutic benefits. Various growth
factor-specific strategies are depicted (broken
arrows) that could be selected to either enhance (+)
or inhibit (-) the chosen growth factor function.
ECM, extracellular matrix.
Centre for Cell and Molecular Medicine,
Keele University School of Medicine, North Staffordshire
Hospital, Stoke-on-Trent, UK
Former
InterMune CEO W. Scott Harkonen Indicted for
Wire Fraud and FDA Violations
SAN FRANCISCO, March 18 /PRNewswire-USNewswire/
-- W. Scott Harkonen, M.D., the
former CEO of InterMune Inc., was
indicted on wire fraud and felony
Food, Drug and Cosmetic Act charges
for his role in the creation and
dissemination of false and
misleading information about the
efficacy of InterMunes drug
Actimmune (Interferon gamma-1b) as a
treatment for idiopathic pulmonary
fibrosis (IPF), the Justice
Department announced today.
The indictment alleges that
Harkonen, a medical doctor, was the
chief executive officer of InterMune
from February 1998 through June 30,
2003, and a member of InterMunes
board of directors from February
1998 through September 2003. Under
Harkonen's direction, InterMune
marketed and sold Actimmune to treat
IPF, a fatal disease, despite the
fact that the drug was not approved
by the Food and Drug Administration
(FDA) as a safe and effective
treatment.
According to the indictment,
Harkonen promoted and caused the
promotion by InterMune of Actimmune
as a safe and effective treatment
for IPF, despite the lack of FDA
approval, in order to sell more
Actimmune and to generate revenues
and profits from sales of the
pharmaceutical for InterMune. The
cost of Actimmune for one IPF
patient for one year was
approximately $50,000 and the vast
majority of the companys sales of
Actimmune were for the unapproved,
off-label use of treating IPF.
The indictment further states
that Harkonen devised a scheme to
induce doctors to prescribe, and
patients to take, Actimmune to treat
IPF. As part of that scheme to
defraud, on Aug. 28, 2002, InterMune
issued a press release publicly
announcing the results of a clinical
trial of Actimmune for the treatment
of IPF. Although the clinical trial
in fact failed, Harkonen caused the
issuance and distribution of a false
and misleading press release to
portray that the results of the
trial established that Actimmune
helped IPF patients live longer.
Specifically, the press release's
headline falsely stated that,
InterMune Announces Phase III Data
Demonstrating Survival Benefit of
Actimmune in IPF, with the
subheading Reduces Mortality by 70%
in Patients With Mild to Moderate
Disease.
According to the indictment, it
was part of the scheme to defraud
that the information in the press
release be conveyed to pharmacies
that sold Actimmune and to patients
and doctors. In furtherance of this
scheme, defendant Harkonen caused a
specialty pharmacy to distribute the
misleading information in the press
release to more than 2,000
pulmonologists and to patients
taking Actimmune.
In October 2006, InterMune agreed
to enter into a deferred prosecution
agreement and to pay nearly $37
million to resolve criminal charges
and civil liability in connection
with the illegal promotion and
marketing of its drug Actimmune.
InterMune also entered into a 5-year
Corporate Integrity Agreement with
the Office of Inspector General for
the Department of Health and Human
Services.
When corporate executives provide
false and misleading information
about pharmaceuticals, they
jeopardize the public health and
welfare, said Jeffrey S. Bucholtz,
acting Assistant Attorney General
for the Civil Division. The
Department of Justice is committed
to ensuring that patients and their
doctors receive truthful information
about medical products and will hold
accountable those individuals who
are responsible for sending the
public deceptive information.
The U.S. Attorney's Office for
the Northern District of California
is committed to protecting the
public against health care fraud,
said Brian J. Stretch, acting U.S.
Attorney. Those who unlawfully
violate the trust that exists among
the biotechnology industry, the FDA,
doctors and patients will be
prosecuted.
The maximum statutory penalty for
wire fraud is 20 years in prison, a
$250,000 fine, three years
supervised release, and $100
mandatory special assessment. The
maximum statutory penalty for acting
with intent to defraud and mislead,
resulting in drugs being misbranded
while held for sale after shipment
in interstate commerce, is three
years in prison, a $250,000 fine,
one year supervised release, and
$100 mandatory special assessment.
However, any sentence following
conviction would be imposed by the
court after consideration of the
U.S. Sentencing Guidelines and the
federal statute governing the
imposition of a sentence. Harkonen
is scheduled to be arraigned on
Friday, March 28, 2008, at 9:30 a.m.
before the Hon. Magistrate Judge
Joseph C. Spero.
Pharmaceutical executives who
promote drugs using false and
misleading information should not be
allowed to hide behind a corporate
shield, said Kim Rice, Special Agent
in Charge of FDA's Office of
Criminal Investigations, Washington
Field Office. Pharmaceutical
companies do not run themselves, and
those who engage in criminal conduct
will be held personally accountable.
We have an obligation to pursue
and bring to justice those who prey
on the vulnerable and place profits
before public health, said FBI
Special Agent in Charge Charlene B.
Thornton. This four-year
investigation reflects the
seriousness with which the FBI takes
violations of the law by those
entrusted to safeguard the health of
the public.
The results of this criminal
investigation show our commitment to
protect the Veteran Administrations
healthcare system from deceptive and
fraudulent practices by
pharmaceutical companies, said
Special Agent in Charge Douglas J.
Carver of the U.S. Department of
Veterans Affairs, Office of
Inspector General. These charges are
the result of a multi-year
investigation by the Federal Bureau
of Investigation; the Food and Drug
Administration's Office of Criminal
Investigations; the Department of
Veterans Affairs' Office of
Investigations; and the Office of
Personnel Management's Office of
Investigations.
This case is being prosecuted by
Assistant U.S. Attorney Ioana Petrou
of the Northern District of
California and trial Attorneys
Sondra Mills and Allan Gordus of the
Office of Consumer Litigation in the
Civil Division in Washington with
the assistance of Associate Chief
Counsel Anne Walsh of the FDA Office
of General Counsel, Paralegal
Specialists Maryam Beros and Matthew
McCrobie, and Legal Technician Ana
Guerra.
An indictment contains only
allegations against an individual
and, as with all defendants, the
defendant in this case must be
presumed innocent unless and until
proven guilty.
SOURCE U.S. Department of Justice
Contact: U.S. Department of
Justice Office of Public Affairs,
+1-202-514-2007, TDD,
+1-202-514-1888
How Can We Develop New Treatments
For
Idiopathic Pulmonary Fibrosis?
04 Mar 2008
Idiopathic pulmonary fibrosis (IPF)
is a devastating lung disorder of
unknown cause that leads to death in
a relatively short time because of
the lack of any effective treatment.
In an article in this week's PLoS
Medicine, a team of researchers
from Mexico and the US discusses how
a better understanding of the
molecular pathways involved in
causing IPF may lead to the
development
of new therapies.
Moisés Selman (Instituto Nacional de
Enfermedades Respiratorias, Mexico
City, Mexico) and colleagues say
that the lungs of patients with IPF
are enriched with genes associated
with lung development in the embryo.
In healthy adults, these genes are
switched off but they appear to
be abnormally switched on in IPF.
"Dysfunctional activation of
embryological pathways regularly
repressed in the adult life may
explain the persistent nature of the
disease," say the authors.
"Designing and implementing
interventions that target these
embryological pathways may be
required to develop novel anti-IPF
therapies and to significantly
improve the outcome of IPF
patients."
Citation: Selman M, Pardo A,
Kaminski N (2008) Idiopathic
pulmonary fibrosis: Aberrant
recapitulation of developmental
programs? PLoS Medicine 5(3):
e62.
CONTACT:
Moisés Selman
Instituto Nacional de Enfermedades
Respiratorias
Tlalpan 4502
Mexico City, DF 14080
Mexico
New organ-transplant method
could eliminate rejection drugs
Jan. 24, 2008: LOS ANGELES - In what is being called a major
advance in organ transplants, doctors say they have
developed a technique that could free many patients from
having to take anti-rejection drugs for the rest of their
lives.
The treatment involved weakening the patient's immune
system, then giving the recipient bone marrow from the
person who donated the organ. In one experiment, four of
five kidney recipients were off immune-suppressing medicines
up to five years later.
"There's reason to hope these patients will be off drugs for
the rest of their lives," said Dr. David Sachs of
Massachusetts General Hospital in Boston, who led the
research published in today's New England Journal of
Medicine.
Since the world's first transplant more than 50 years ago,
scientists have searched for ways to trick the body to
accept a foreign organ as its own. Immune-suppressing drugs
that prevent organ rejection came into wide use in the
1980s. But they raise the risk of cancer and kidney failure.
And they have side effects such as excessive hair growth,
bloating and tremors.
Acid
Reflux Study Looks At Lifespan Of
Sufferers
Jan. 4th, 2008: Gastroesophageal reflux
disease (GERD), often known as acid
reflux, is a common problem that has
been associated with cancers, asthma,
recurrent aspiration and pulmonary
fibrosis. A new study published in
The American Journal of Gastroenterology
examines whether GERD sufferers may have
shorter lifespans than those without the
disease.
Drawing on over 50,000 person-years of
data, the study provides reassuring
evidence that people with acid reflux
symptoms do not have an increased risk
of death, finding no difference in
survival rates between sufferers and
non-sufferers.
In fact, the study finds that people
with infrequent acid reflux may actually
have better survival rates than those
with either daily symptoms, or none at
all. "It may be that occasional reflux
symptoms are a reflection of potential
protective behaviors that are associated
with reflux, such as regular exercise or
modest amounts of alcohol ingestion,"
suggest Nicholas J. Talley and G.
Richard Locke, III, co-authors of the
study.
The study adds perspective to the risk
of acid reflux symptoms. While there are
a large number of acid reflux sufferers
in the U.S., incidences of related
cancer are extremely rare. "Although
extraesophageal manifestations occur in
some people with reflux disease, our
results suggest that this disease is a
benign condition in the vast majority of
sufferers," say the authors.
This
study is published in The American
Journal of Gastroenterology.
Nicholas J. Talley, M.D.,
Ph.D., is Editor-in-Chief of The
American Journal of Gastroenterology; a
Professor of Medicine and Epidemiology
at the Mayo Clinic College of Medicine;
and Chair of the Department of Internal
Medicine at the Mayo Clinic,
Jacksonville.
G. Richard Locke, III, M.D., is a
Professor of Medicine at the Mayo Clinic
College of Medicine; Consultant,
Division of Gastroenterology and
Hepatology, Department of Internal
Medicine; and Consultant, Division of
Health Care Policy & Research,
Department of Health Sciences Research
at the Mayo Clinic.
Translational
research patented first experimental treatment against
idiopathic pulmonary fibrosis
Innovative pneumocytes
transplantation has reverted the disease for the first time in
rats
21-Dec-2007 Barcelona, Spain:
Idiopathic pulmonary fibrosis is a disease with
unknown cause with a very severe prognosis; when detected, it is
already in an advanced stage. Patients suffering from it cannot
develop with normality pulmonary gas exchange, and have a very
reduced quality of life. Because of lack of an effective
treatment, they rarely survive 5 years after being diagnosed.
Idiopathic pulmonary fibrosis affects 13 out of 100,000 men and
7 out of 100,000 women, normally over 40 years of age.
Researchers from the Biomedical Research Institute of Barcelona
CSIC (IIBB-CSIC), a centre developing research in the framework
of the Institut d’Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), have discovered and patented a method to stop and
revert this disease in an animal model. A clinical study will be
soon conducted in humans in the Hospital Clínic de Barcelona.
Results of their research work are published in the last
issue of the American Journal of Respiratory and Critical
Care Medicine.
This study has had the collaboration of basic researchers, such
as Dr. Anna Serrano-Mollar, and Dr. Oriol Bulbena,
first and last signatories of the study; and researchers with a
clinical background, such as Dr. Antoni Xaubet, from the
Unit of Pneumology of the Hospital Clínic de Barcelona. This
turns this work into a paradigm of translational research
promoted in IDIBAPS and through other initiatives such as the
Network of Centres of Biomedical Research (CIBERs). This
research work has been financed through a contribution from the
Fondo de Investigaciones Sanitarias (FIS) from the Instituto de
Salud Carlos III.
Gas exchange is developed in lungs thanks to type 1
pneumocytes in alveoli, cells recovering the inner walls of the
alveolar cavity. Occupying the same spaces, there are also type
II pneumocytes, precursor cells that repair the damaged alveolar
tissue. When idiopathic pulmonary fibrosis appears, this
regeneration process cannot be developed correctly and fibrosis
advances until respiration is impossible. The technique
developed by researchers from the IIBB-CSIC-IDIBAPS consists in
a transplantation of type II pneumocytes via intratracheal. In
order to monitor correctly the transplanted cells with genetic
and fluorescence techniques, sexual chromosomal differences were
used. Thus, the disease was induced in female rats, and cells
from male rats were transplanted. This is a lowly invasive
technique which has permitted to regenerate, for the first time,
rat fibrotic alveoli where idiopathic pulmonary fibrosis was
induced.
CSIC has patented as a treatment the cell suspension
transplanted with this innovative strategy. The world patent
will be proved in humans with a clinical study, soon conducted
in the Hospital Clínic de Barcelona thanks to the financing of
the Fundación Genoma España and CSIC This study will have the
participation of 6 recently diagnosed patients who will receive
a suspension of type II pneumocytes coming from a dead donor,
since these cells cannot be cultured in the laboratory. All this
events throw new and hopeful light into basic and clinical
research lines. One of the following steps of researchers will
be to try to obtain type II pneumocytes from adult stem cells.
Further information:
Communication Area IDIBAPS
Marc de Semir, Head of Communication (mdesemir@clinic.ub.es)
Àlex Argemí, scientific editor (aargemi@clinic.ub.es)
Tel.: 00 34 93 227 57 00
Fibrosis
can be Stopped,
Cured and
Reversed
Tue 18-Dec-2007,
University of California, San Diego
researchers have proven in animal
studies that fibrosis in the liver can
be not only stopped, but reversed. Their
discovery, to be published in PLoS
Online on December 26, opens the door to
treating and curing conditions that lead
to excessive tissue scarring such as
viral hepatitis, fatty liver disease,
cirrhosis, pulmonary fibrosis,
scleroderma and burns.
University of California, San Diego
researchers have proven in animal studies that
fibrosis in the liver can be not only stopped,
but reversed. Their discovery, to be published
in PLoS Online on December 26, opens the
door to treating and curing conditions that lead
to excessive tissue scarring such as viral
hepatitis, fatty liver disease, cirrhosis,
pulmonary fibrosis, scleroderma and burns.
Six years ago, the UC San Diego School of
Medicine research team discovered the cause of
the excess fibrous tissue growth that leads to
liver fibrosis and cirrhosis, and developed a
way to block excess scar tissue in mice. At that
time, the best hope seemed to be future
development of a therapy that would prevent or
stop damage in patients suffering from the
excessive scarring related to liver or lung
disease or severe burns.
In their current study, Martina Buck, Ph.D.,
assistant professor of medicine at UCSD and the
Veterans Affairs San Diego Healthcare System,
and Mario Chojkier, M.D., UCSD professor of
medicine and liver specialist at the VA, show
that by blocking a protein linked to
overproduction of scar tissue, they can not only
stop the progression of fibrosis in mice, but
reverse some of the cell damage that already
occurred.In response to liver injury – for
example, cirrhosis caused by alcohol – hepatic
stellate cell (HSC) activated by oxidative
stress results in large amounts of collagen.
Collagen is necessary to heal wounds, but
excessive collagen causes scars in tissues. In
this paper, the researchers showed that
activation of a protein called RSK results in
HSC activation and is critical for the
progression of liver fibrosis. They theorized
that the RSK pathway would be a potential
therapeutic target, and developed an RSK
inhibitory peptide to block activation of RSK.
The scientists used mice with severe liver
fibrosis – similar to the condition in humans
with cirrhosis of the liver – that was induced
by chronic treatment with a liver toxin known to
cause liver damage. The animals, which continued
on the liver toxin, were given the RSK-inhibitory
peptide. The peptide inhibited RSK activation,
which stopped the HSC from proliferating. The
peptide also directly activated the caspase or
“executioner" protein, which killed the cells
producing liver cirrhosis but not the normal
cells.“All control mice had severe liver
fibrosis, while all mice that received the RSK-inhibitory
peptide had minimal or no liver fibrosis,” said
Buck. Buck explained that the excessive collagen
response is blocked by the RSK-inhibitory
peptide, but isn’t harmful to the liver. “The
cells continue to do their normal, healing work
but their excess proliferation is controlled,”
Buck said. “Remarkably, the death of HSC may
also allow recovery from liver injury and
reversal of liver fibrosis.”
The researchers found a similar activation of
RSK in activated HSC in humans with severe liver
fibrosis but not in control livers, suggesting
that this pathway is also relevant in human
liver fibrosis. Liver biopsies from patients
with liver fibrosis also showed activated RSK.
The study expands on work reported in 2001 in
the journal Molecular Cell announcing that a
team led by Buck had found that a small piece of
an important regulatory protein called C/EBP
beta was responsible for fibrous tissue growth,
or excessive scar tissue following injury or
illness. When normal scarring goes awry,
excessive build-up of fibrous tissue can produce
disfiguring scars or clog vital internal organs
and lead to serious complications. Buck and
colleagues developed a mutated protein that
stopped this excessive fibrous tissue growth.
“Six years ago, we showed a way to prevent or
stop the excessive scarring in animal models,”
said Buck. “Our latest finding proves that we
can actually reverse the damage.” Worldwide,
almost 800,000 people die from liver cirrhosis
each year, and there is currently no treatment
for it. Excessive tissue repair in chronic liver
disease induced by viral, toxic, immunologic and
metabolic disorders all result in excessive scar
tissue, and could benefit from therapy developed
from the UCSD researchers’ findings.The research
was supported by grants from the National
Institutes of Health, the Department of Veterans
Affairs and UCSD’s Medical Research Foundation.
Buck is the recipient of a Howard Temin Award
from the National Cancer Institute.
Molecular pathway
appears crucial in development of pulmonary fibrosis
Discovery may
provide new therapeutic target for dangerous lung
disease
Massachusetts
General Hospital
12-Dec-2007 A study led by Massachusetts General
Hospital (MGH) researchers may have found a key
mechanism underlying idiopathic pulmonary fibrosis (IPF),
a usually fatal lung disease for which
transplantation is the only successful treatment.
The investigators found that a specific molecular
pathway appears responsible for key aspects of the
scarring of lung tissue that characterizes IPF, the
cause of which is currently unknown. The results
will appear in the January issue of Nature Medicine
and have received early online release.
“Identifying the key role of this pathway in the
development of fibrosis gives us an exciting new
target for devising treatments,” says Andrew Tager,
MD, of the MGH Pulmonary and Critical Care Unit, who
led the study. “An agent that blocks this pathway is
already being developed as a potential cancer
treatment, and we’re hoping to be able to test it in
our animal model of IPF to determine whether it
might be a candidate for trials in patients.”
About 50,000 new cases of IPF are diagnosed in
the U.S. each year, primarily in people aged 50 to
75. While some patients may survive for extended
periods, in others the diseases progresses rapidly,
leading to death in an average of 3 to 5 years.
Theories about the cause of IPF previously focused
on chronic inflammation of the lungs, but recent
evidence has suggested that an abnormal healing
response to some sort of lung injury may be
responsible.
The primary characteristic of IPF is scarring
(fibrosis) of the lung surface, rendering it unable
to transmit oxygen into the bloodstream. In any part
of the body, scarring occurs when cells called
fibroblasts, an important part of normal wound
healing, make collagen to reinforce the healing
matrix that forms over damaged tissue. Normally
scarring is limited, but if too many fibroblasts
travel to the site of an injury, large amounts of
collagen can be deposited, producing excessive,
fibrotic scarring. Fibroblasts are known to be
present in affected lung tissue in IPF, and previous
studies showed that the activity of factors that
attract fibroblasts to the site of an injury rises
with the severity of the disease. The current study
was designed to determine which specific
“chemoattractants” were associated with IPF,
something not previously known.
Analysis of fluid from the lung surfaces of a
mouse model of pulmonary fibrosis suggested that the
activity of lysoposphatidic acid (LPA), acting
through its receptor LPA1, was responsible for
attracting fibroblasts in the disorder. This
association was supported by the fact that a strain
of mice lacking the gene for LPA1 did not develop
pulmonary fibrosis when treated with a compound that
usually causes the disease in the animals. Lung
fluid samples from human IPF patients not only had
significantly higher levels of LPA than control
samples, laboratory tests showed that patient
samples attracted fibroblasts while fluid from
controls did not. In addition, an agent that blocks
the LPA1 receptor eliminated the ability of fluid
from IPF patients to attract fibroblasts.
“These results indicate that the LPA-LPA1 pathway
is responsible for the abnormal migration of
fibroblasts into the lungs in IPF, an absolutely
crucial step in the development of fibrosis,” says
Andrew Luster, MD, PhD, senior author of the study.
“This pathway appears to be involved in several
steps in the development of fibrosis, including the
leaking of blood vessels, which is why the LPA1
knockout mice are so dramatically protected. If
we’re right, then targeting this pathway should be a
very exciting new therapeutic strategy for IPF.”
Luster is director of the MGH Center for Immunology
and Inflammatory Disease (CIID) and a professor of
Medicine at Harvard Medical School (HMS). Tager is
also associated with the MGH CIID and has opened a
clinic focused on pulmonary fibrosis and related
lung diseases. He is an assistant professor of
Medicine at HMS.
Additional co-authors of the study are Peter
LaCamera, Barry Shea, Gabriele Campanella, John Wain,
Banu Karimi-Shah, Nancy Kim, and William Hart, of
the MGH; Moises Selman, National Institute for
Respiratory Disorders, Mexico; Zhenwen Zhao, and Yan
Xu, Indiana University School of Medicine; Vasiliy
Polosukhin, and Timothy Blackwell, Vanderbilt
University School of Medicine; Annie Pardo, National
Autonomous University of Mexico; and Jerold Chun,
Scripps Research Institute. The study was supported
by grants from the Pulmonary
Fibrosis Foundation, the American Lung
Association, the Nirenberg Center for Advanced Lung
Disease, the National Autonomous University of
Mexico, and the U.S. National Institutes of Health.
Breakthrough
brings hope to Seattle scientists
UW to get cells early next year
Seattle
Wednesday, November 21, 2007
Tuesday's announcement that scientists have
created the equivalent of embryonic stem cells without
using an embryo has Seattle researchers cautiously
optimistic about the future of stem cell research in the
area. The research was published online by two journals,
Cell and Science. The Cell paper is from a team at Kyoto
University in Japan; the team published by Science was
from the University of Wisconsin-Madison.
Dr. Chuck Murry, a pathology professor at the
University of Washington, said he wrote to both groups
asking for cells to be sent to the university. The
Wisconsin scientists agreed to send them, probably by
the first of the year, he said. Murry's protocol for
regenerating damaged hearts in rats using embryonic stem
cells was used by the Japanese scientists whose work was
reported in Cell, he said.
"My intention is to get these cells in Seattle and do
what we want to do with them," Murray said. "I'm
cautiously enthusiastic ... things have been wrong
before and if it's not reproducible it's not science ...
but two very good labs have published (the same
findings) in two very good journals." Dr. Beverly
Torok-Storb, a stem cell scientist at the Fred
Hutchinson Cancer Research Center, said she and many
other scientists have been expecting this announcement
for some time. She pointed out that scientists still
must prove the cells are as good as embryonic stem cells
over the long haul. She cautioned against the public
expecting immediate cures and said the next step will be
to try to make certain the cells are safe for humans.
"Will they really be as good and as long-lived as an
embryonic stem cell? We don't know that yet," she said.
Seattle was home many years ago to the first
successful medical use of stem cells, a kind of master
cell that can grow into any one of the body's more than
200 cell types. This allows them to replace cells that
have died and they have been used to replace defective
cells and tissues in patients who have certain diseases
or defects. Scientists at the Hutch are conducting
similar research using canine cells, Torok-Storb said.
Virginia Mason Medical Center also is involved in stem
cell research. Torok-Storb said the findings, which used
human skin cells, eliminate the ethical and moral
dilemma of using human embryonic stem cells for research
and makes every patient his or her own donor with no
worries of rejection. The findings also could mean that
someday two separate lab designs would no longer be
needed at the University of Washington's Institute for
Stem Cell and Regenerative Medicine, Murray said.
Scheduled to open in July 2008, one side would be used
to work only on the federally approved, non-embryonic,
stem cells; the other side for any kind of stem cells.
The findings also increase the potential for more
federal funding, which now is restricted for embryonic
stem cell research, Murray said. "If these cells are the
real deal, which I think they are, there's no reason why
anyone could object to them," he said. "We'll see how
this plays out."
MC3
received
NHLBI
Phase
I
STTR
grant
to
develop
a
novel
pump-oxygenator
with
University
of
Maryland
MC3, Inc. (Ann
Arbor,
MI)
has
announced
the
award
of a
$200,000
Phase
I
Small
Business
Technology
Transfer
Research
(STTR)
grant
from
the
National
Heart,
Lung
and
Blood
Insitute
(NHLBI)
to
develop
a
novel,
paracorporeal
pump-oxygenator
(PPO)
system
to
treat
lung
disease,
which
is
the
third
leading
cause
of
death
in
the
United
States.
The
grant
represents
a
technology
transfer
partnership
between
the
University
of
Maryland
Artificial
Organs
Laboratory
(UMAOL,
Baltimore,
MD)
and
MC3,
Inc.
The
University
of
Maryland
Artificial
Organs
Laboratory
has
extensive
experience
in
developing
compact
impeller
based
blood
pumps,
and
the
grant
will
concentrate
on
integrating
a
compact,
rotating
impeller
into
the
central