Hindawi Publishing Corporation
Volume 2007, Article ID 71323, 10 pages
The Role of PPARs in Lung Fibrosis
Heather F. Lakatos,1,2Thomas H. Thatcher,2,3R. Matthew Kottmann,2,3Tatiana M. Garcia,2,4
Richard P. Phipps,1,2,4and Patricia J. Sime1,2,3
1Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA
2Lung Biology and Disease Program, University of Rochester, Rochester, NY 14642, USA
3Department of Medicine, University of Rochester, Rochester, NY 14642, USA
4Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA
Received 14 February 2007; Accepted 18 May 2007
Recommended by Jesse Roman
Pulmonary fibrosis is a group of disorders characterized by accumulation of scar tissue in the lung interstitium, resulting in loss
of alveolar function, destruction of normal lung architecture, and respiratory distress. Some types of fibrosis respond to corticos-
teroids, but for many there are no effective treatments. Prognosis varies but can be poor. For example, patients with idiopathic
pulmonary fibrosis (IPF) have a median survival of only 2.9 years. Prognosis may be better in patients with some other types of
pulmonary fibrosis, and there is variability in survival even among individuals with biopsy-proven IPF. Evidence is accumulating
that the peroxisome proliferator-activated receptors (PPARs) play important roles in regulating processes related to fibrogenesis,
including cellular differentiation, inflammation, and wound healing. PPARα agonists, including the hypolidipemic fibrate drugs,
inhibit the production of collagen by hepatic stellate cells and inhibit liver, kidney, and cardiac fibrosis in animal models. In the
mouse model of lung fibrosis induced by bleomycin, a PPARα agonist significantly inhibited the fibrotic response, while PPARα
knockout mice developed more serious fibrosis. PPARβ/δ appears to play a critical role in regulating the transition from inflam-
mation to wound healing. PPARβ/δ agonists inhibit lung fibroblast proliferation and enhance the antifibrotic properties of PPARγ
agonists. PPARγ ligands oppose the profibrotic effect of TGF-β, which induces differentiation of fibroblasts to myofibroblasts, a
critical effector cell in fibrosis. PPARγ ligands, including the thiazolidinedione class of antidiabetic drugs, effectively inhibit lung
fibrosis in vitro and in animal models. The clinical availability of potent and selective PPARα and PPARγ agonists should facilitate
rapid development of successful treatment strategies based on current and ongoing research.
Copyright © 2007 Heather F. Lakatos et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Pulmonary fibrosis is a potentially fatal disease character-
ized by accumulation of scar tissue in the lung interstitium,
resulting in loss of alveolar function, destruction of nor-
mal lung architecture, and respiratory distress [1–3]. Known
as silica and asbestos, chemo- and radiation therapy, au-
toimmunity, hypersensitivity pneumonitis, and sarcoidosis
[4, 5]. The idiopathic interstitial pneumonias, as the name
the commonest of which is the usual intersitial pneumonitis
(UIP), also called idiopathic pulmonary fibrosis (IPF) [6–8].
Some types of fibrosis respond to corticosteroids but many
are refractory [9–11]. Prognosis is varied, but can be poor.
UIP is considered to be the most severe of the idiopathic in-
terstitial pneumonias. However, there is significant variabil-
ity in the natural history of this disease. For example, the
mean survival time after a diagnosis of UIP is less than three
years , but there are patients who can survive for much
longer periods of time with much slower (or rarely no) pro-
gression of their lung disease . In contrast, other patients
can develop acute exacerbations of their pulmonary fibrosis
ities, respiratory failure, and death in 20%–86% of patients.
Histological examination of their lungs reveals diffuse alveo-
lar damage superimposed on a background of UIP . The
etiology of these exacerbations is unclear, but factors includ-
ing infection have been implicated.
At the cellular level, pulmonary fibrosis is character-
ized by proliferation and accumulation of fibroblasts and
scar-forming myofibroblasts in the lung interstitium with
increased synthesis and deposition of extracellular matrix
fibroblasts were previously regarded as simple structural
cells, they are now recognized as having important sentinel
and regulatory functions and are a rich source of regula-
tory cytokines and chemokines . Fibroblasts differentiate
to myofibroblasts after appropriate stimuli, including trans-
forming growth factor (TGF)-β1 [9, 14, 16]. Myofibrob-
lasts have some of the characteristics of smooth muscle cells,
including contractility and expression of α-smooth muscle
actin (α-SMA) [14, 17, 18]. The differentiation of fibroblasts
to myofibroblasts, along with increased cellular proliferation
and matrix deposition, leads to the development of fibrob-
lastic foci similar in appearance to the early stages of nor-
mal wound healing. Fibrosis is usually progressive, leading to
destruction of the normal lung architecture [2, 14, 17, 18].
Other organs can develop fibrosis, including the skin, liver,
kidney, and pancreas, and the cellular events and signals are
likely to be similar.
It has been hypothesized that fibrosis is a consequence
of abnormal regulation of wound repair [2, 19, 20]. An in-
phase in which fibroblasts and myofibroblasts at the injury
site replace damaged tissue with scar tissue. Normally, this
phase of wound repair is self-limiting, with myofibroblasts
eventually undergoing apoptosis, and the scar tissue may
be remodeled and reconstructed as relatively normal func-
not undergo apoptosis, but continue to proliferate, resulting
in progressive scarring. The cellular signals involved in the
maintenance of the profibrotic phenotype are unknown, al-
though it is likely that TGF-β is a critical factor [21–24].
2. PPARs AND LUNG DISEASE
Peroxisome proliferator-activated receptors (PPARs) are
ligand-activated transcription factors belonging to the nu-
clear hormone receptor family, that function to regulate a
wide range of physiological activities . Three different
isoforms of PPARs have been identified: PPARα (NR1C1),
PPARβ/δ (NUC1; NR1C2), and PPARγ (NR1C3), encoded
by three separate genes. The PPARs and their obligate core-
ands. The ligand-activated heterodimeric complexes then in-
ators response elements (PPREs) in their promoters. PPARα
was first identified as the mediator of the response to per-
oxisome proliferators in rodents . Over the past decade,
PPARs have been implicated as important regulators of var-
ious physiological processes, such as lipid and lipoprotein
metabolism, glucose homeostasis, cellular proliferation, dif-
ferentiation, and apoptosis. PPARα is found in high levels in
liver, kidney, heart, and muscle, whereas PPARβ/δ is ubiq-
uitously expressed [26, 27]. PPARγ is found in two main
isoforms, PPARγ1 and PPARγ2, derived from different pre-
mRNA splice variants that use different transcription start
sites. PPARγ is widely expressed, and has been found in
blood cells, such as macrophages , T and B lympho-
cytes [29, 30], and platelets , as well as in tissues in-
cluding adipose, colon, spleen, retina, skeletal muscle, liver,
bone marrow, and lung . Within the lung, PPARγ is ex-
pressed by the epithelium, smooth muscle cells, fibroblasts,
endothelium, macrophages, eosinophils, and dendritic cells
The role of the PPARs in lung disease is not yet clear.
Both PPARα and PPARγ have been localized in lung tis-
sue, including bronchial epithelial cells, alveolar walls, and
alveolar macrophages [27, 32, 33]. A comparison of non-
smokers, smokers with chronic obstructive pulmonary dis-
ease (COPD), and smokers without COPD found no statisti-
cally significant difference in the number of PPARγ-positive
macrophages, but found an increased number of PPARα-
positive alveolar macrophages in smokers with COPD .
Sarcoidosis and pulmonary alveolar proteinosis are two
other disorders in which alveolar macrophages are defi-
cient in PPARγ .A causal relationship has not been de-
termined, however, treatment of pulmonary alveolar pro-
teinosis with granulocyte-macrophage colony-stimulating
factor (GM-CSF) restores alveolar macrophage PPARγ levels
There is evidence that the PPARs, particularly PPARα
and PPARγ, play a role in regulating inflammation. For ex-
ample, fatty-acid-derived inflammatory mediators, includ-
ing prostaglandins and leukotrienes, are ligands for PPARα
and γ . Although the pathogenesis of fibrosis appears to
be distinct from inflammation, and many forms of fibrosis
are refractory to anti-inflammatory therapies such as corti-
costeroids, recent work has supported the hypothesis that fi-
brosis is a consequence of a dysregulated wound healing pro-
cess with an initial injury and inflammatory response. Cer-
tainly, many important inflammatory signals and mediators,
particularly TGF-β, TNF-α, and IL-1β, and prostaglandins,
play key roles in fibrosis [21–24]. This review will discuss re-
cent reports examining the link between PPARs and fibrosis,
and the possibility of using PPAR ligands as antifibrotic ther-
apies. Because the study of PPARs in lung fibrosis is relatively
new, we will also review selected results from fibrotic disease
models in other organs.
PPARα was originally cloned as the molecular target for
the hypolipidemic fibrate drugs, although arachidonic acid
metabolites (eicosanoids, prostaglandins, and leukotrienes)
are also important ligands . PPARα plays a key role in
lipid metabolism and is highly expressed in tissues involved
in lipid and cholesterol metabolism, including the liver, kid-
ney, and macrophages. PPARα ligands have important anti-
inflammatory properties, although some studies have re-
ported proinflammatory effects as well [37, 39]. Little is
known about PPARα in lung disease, although other fibro-
sis models implicate PPARα in regulating fibrosis.
dramatically reduced fibrosis in the thioacetamide model
of cirrhosis . N-3 polyunsaturated fatty acid, another
PPARα ligand, reduced hepatic and serum TNF-α levels and
reduced the degree of liver injury in a rat model of non-
alcoholic steatohepatitis . The synthetic PPARα agonist
Heather F. Lakatos et al.3
WY14643 reduced the severity of steatohepatitis in C57BL/6
mice fed a methionine- and choline-deficient diet, with re-
ductions in hepatic mRNA levels of collagen alpha 1, tissue
inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, and
matrix metalloproteinase (MMP)-13 .
Fenofibrate also attenuated cardiac and vascular fibro-
sis in pressure-overloaded rat hearts, with reductions in
collagen I and III mRNA , and inhibited fibrotic left
ventricular remodeling in mineralcorticoid-dependent hy-
pertension . The PPARα agonist gemfibrozil attenu-
ated glomerulosclerosis and collagen deposition in diabetic
ApoE-knockout mice .
Recent reports have found significantly reduced PPARα
mRNA levels in lymphocytes from cystic fibrosis patients
, while PPARα knockout mice develop more severe
carageenan-induced pleural inflammation , suggesting a
connection between diminished PPARα-dependent gene ac-
tivation and disease pathology.
The role of PPARα in lung fibrosis was investigated in
mice using the bleomycin model of lung injury and fi-
brosis. Intratracheal instillation of the antineoplastic agent
severe fibrosis, with proliferation of α-SMA-positive myofi-
broblasts, increased collagen deposition, and loss of normal
alveolar architecture [48, 49]. PPARα-knockout mice treated
with bleomycin developed more severe inflammation and
fibrosis than wild-type mice, with increased immunohisto-
chemical detection of TNF-α and IL-1β, increased apoptosis
of interstitial cells, and decreased survival . Treatment of
wild-type mice with the PPARα agonist WY-14643 enhanced
survival and reduced the severity of fibrosis, as well as reduc-
ing the detection of TNF-α and apoptosis by immunohisto-
chemistry. The authors concluded that endogenous PPARα
ligands play an important role in limiting the fibrotic re-
sponse in wild-type mice, and that treatment with PPARα
ligands has potential as an antifibrotic therapy.
As yet, there have been no molecular mechanisms pro-
posed to explain these results. Since bleomycin treatment re-
sults in an acute inflammatory response that later resolves
into fibrosis, it is possible that PPARα agonists act to inhibit
fibrosis by moderating the initial inflammatory response.
This could be addressed by using a fibrogenic insult that pro-
vokes minimal inflammation, such as adenovirus-mediated
overexpression of TGF-β .
Interestingly, there is some evidence that the effects
of PPARα agonists are not entirely dependent on PPARα-
dependent transcription . Since the above study did not
report treating PPARα-knockout mice with WY-14643, the
issue of the PPARα dependence or independence of the ef-
fect was not addressed. It should also be noted that WY-
14643 is also a weak PPARγ agonist , and PPARγ ago-
nists may have antifibrotic activity as well (discussed below).
One way to investigate the PPARα dependence or indepen-
dence of PPARα agonists would be to study their effects in
PPARα-knockout fibroblasts in vitro and PPARα-knockout
mice in vivo. Studies using additional in vivo models of fi-
brosis (such as thoracic radiation or inhalation of crystalline
silica) should also prove informative.
Although little is known about PPARβ/δ in the lung,
PPARβ/δ does play a critical role in wound healing in
the skin. PPARβ/δ expression is upregulated following skin
injury. Further, PPARβ/δ-knockout mice exhibit defective
in vivo wound healing, and keratinocytes from PPARβ/δ-
knockout mice show decreased adhesion and migration in
vitro . It has been suggested that PPARβ/δ is a critical
regulator of the transition from the initial inflammatory re-
sponse to the later wound healing program .
An intriguing recent study suggested that PPARβ/δ
may be a target of prostacyclin mimetics used in treating
pulmonary hypertension. Treprostinil sodium activated a
PPARβ/δ reportergeneandinhibited proliferationoflungfi-
broblasts in vitro. The effect was not seen in lung fibroblasts
from PPARβ/δ-knockout mice, demonstrating that the effect
was dependent on PPARβ/δ and not on the prostacyclin re-
ceptor . Finally, PPARβ/δ agonists enhance the efficacy
of PPARγ agonists in mediating adipocyte differentiation in
vitro , suggesting that PPARβ/δ agonists may also po-
tentiate the antifibrotic effects of PPARγ agonists discussed
PPARγ is expressed in many types of lung cells includ-
ing fibroblasts, ciliated airway epithelial cells and alveolar
type II pneumocytes, alveolar macrophages, T lymphocytes,
and airway smooth muscle cells . Endogenous ligands
of PPARγ include 15-deoxy −Δ12,14-prostaglandin J2(15d-
PGJ2) [58, 59], lysophosphatidic acid , and nitrolinoleic
acid . PPARγ can also be activated by synthetic ligands
insulin-sensitizing drugs  including rosiglitizone and pi-
oglitizone, as well as oleanic acid derivatives known as triter-
The anti-inflammatory properties of PPARγ ligands have
been well described [37, 64]. In the lung, PPARγ ligands in-
hibit LPS-induced neutrophilia [65, 66] and allergic airway
inflammation and hyperresponsiveness in a mouse model
of asthma [67, 68]. PPARγ ligands also inhibit the release
of proinflammatory mediators from airway epithelial cells
and alveolar macrophages [69, 70]. In addition, PPARγ plays
an important role in regulating cellular differentiation, as
PPARγ ligands promote differentiation of preadipocyte fi-
broblasts to adipocytes [58, 59, 71].
A number of studies have investigated PPARγ ligands
as potential antifibrotic agents in vivo. Pioglitazone reduced
carbon-tetrachloride-induced hepatic fibrosis in rats, with
decreases in hydroxyl proline content, procollagen I mRNA,
and α-SMA-positive hepatic stellate cells . A similar ef-
fect was observed when fibrosis was induced by a choline-
deficient diet [73, 74]. Rosiglitazone inhibits cardiac fibro-
sis in rats  and kidney fibrosis in diabetic mice and rats
. Intriguingly, improvements in renal function have been
noted in patients with type II diabetes who are treated with
TZDs [75, 76].
4 PPAR Research
Adipocyte Undifferentiated fibroblastMyofibroblast
(center panel) can be differentiated to adipocyte-like cells (left panel) by treatment with 1 μM 15d-PGJ2for 8 days. Lipid droplets were
visualized with oil red O staining. Alternatively, incubation with 10 ng/mL TGF-β for 3 days will differentiate fibroblasts to myofibroblasts
(right panel). α-SMA was detected by immunocytochemistry. Note the long bundles of contractile fibers.
Only a limited amount of data is available on the effects
of PPARγ agonists on lung fibrosis in vivo. Ciglitazone ad-
ministered by nebulization in a mouse model of asthma not
only reduced lung inflammation and eosinophilia, but also
reduced basement membrane thickening and collagen depo-
sition associated with airway remodeling, as well as synthesis
of the profibrotic cytokine TGF-β . This effect was abol-
ished by concomitant use of GW9662, an irreversible PPARγ
mortality, inflammation, cellular infiltrates, and histological
fibrosis following intratracheal administration of bleomycin
. Studies of the in vivo effects of PPARγ agonists have
been hampered by the fact that unlike PPARα, homozygous
germline deletion of the PPARγ gene results in embryonic
lethality . A conditional knockout mouse, in which exon
2 of the PPARγ gene has been flanked by loxP sites, has been
developed , and strategies to inducibly knock out PPARγ
expression in the adult mouse lung prior to fibrotic insult are
being explored in a number of laboratories.
The antifibrotic effects of PPARγ ligands have been stud-
ied in vitro, leading to new insights into their mechanism of
action. As previously discussed, TGF-β drives differentiation
of lung fibroblasts to myofibroblasts, a key effector cell in fi-
brosis [16, 23, 24]. In contrast, PPARγ ligands differentiate
fibroblasts to fat-storing adipocytes [58, 59]. This suggests
β (Figure 1). We investigated the ability of PPARγ ligands to
counter the profibrotic effects of TGF-β on primary human
lung fibroblasts. Rosiglitazone and 15d-PGJ2 efficiently in-
hibited TGF-β-driven differentiation of human lung fibrob-
lasts to myofibroblasts, with reductions in the expression of
α-SMA (a myofibroblast marker) and production of collagen
Similar results have been observed in other cell types.
Differentiation of hepatic stellate cells to a myofibroblast
phenotype is a key step in liver fibrosis [80–82]. PPARγ
agonists suppress proliferation of hepatic stellate cells and
chemotaxis in response to platelet-derived growth fac-
tor (PDGF) , and induce hepatocyte growth factor
(HGF), an anti-fibrotic cytokine . PPARγ ligands also
block PDGF-dependent proliferation, prolyl4-hydroxylase
(α) mRNA, and the expression of collagen and α-SMA by
pancreatic stellate cells . Renal cortical fibroblasts treated
with glucose induce myofibroblastic markers. Treatment of
these cells with pioglitizone decreased collagen IV produc-
tion, incorporation of proline, fibronectin production, and
MMP-9 activity as well as reduced secretion of TIMP-1 and
-2 [86, 87].
The molecular mechanisms by which PPARγ ligands in-
hibit myofibroblast differentiation and effector function are
brotic cytokine in lung fibrosis [2, 21], several groups have
investigated the ability of PPARγ ligands to interfere with
TGF-β signaling. TGF-β signaling is mediated by the Smad
2 TGF-β receptor recruits type 1 TGF-β receptors (TGF-βR-
I), forming a heterotetrameric structure that phosphorylates
Smad2 and Smad3. Smad2 and Smad3 form heteromeric
complexes with Smad4, which translocate to the nucleus
and activate transcription of target genes (Figure 2). In hu-
man hepatic stellate cells, TGF-β causes a time- and dose-
dependent increase in Smad3 phosphorylation, followed by
increased collagen production. Cotreatment with either a
TGF-βR-I kinase inhibitor or the synthetic PPARγ agonist
GW7845 resulted in dose-dependent inhibition of both col-
lagen production and Smad3 phosphorylation . In con-
trast, the natural PPARγ agonist 15d-PGJ2 did not inhibit
nuclear translocation of Smad2/3 complexes in human re-
nal mesangial cells treated with TGF-β. Instead, 15d-PGJ2
tor (HGF) via a peroxisome proliferator response element
in the HGF promoter, and upregulated the Smad corepres-
sor TG-interacting factor (TGIF), leading to inhibition of
α-SMA and fibronectin expression . Interestingly, the
same study reported that 15d-PGJ2did inhibit Smad2/3 nu-
β, while we have reported that 15d-PGJ2 does not inhibit
Heather F. Lakatos et al.5
Figure 2: The TGF-β signaling pathway. Binding of TGF-β to TGF-β receptor II recruits TGF-β receptor I (TGF-βR-I). The kinase domain
of TGF-βR-I phosphorylates Smad2 and 3, which form a heteromeric complex with Smad4 that translocates into the nucleus where it
activates transcription of target genes. Numbers indicate points in the pathway where PPARγ ligands have been demonstrated to interfere
with TGF-β signaling. (1) GW7845, a PPARγ ligand, inhibited Smad3 phosphorylation in human hepatic stellate cells . (2) 15d-PGJ2
inhibited nuclear translocation of Smad2/3 in rat kidney fibroblasts . (3) In human renal mesangial cells, 15d-PGJ2induced hepatocyte
growth factor (HGF), which upregulates the Smad corepressor TG-interacting factor (TGIF) . (4) In mouse L929 fibroblasts, 15d-PGJ2
or retinoic acid upregulated the phosphatase and tensin homologue deleted on chromosome 10 (PTEN), leading to repression of TGF-β1
differentiation by PPARγ agonists is mediated by different
mechanisms in different cell types, or that natural and syn-
thetic agonists act by different mechanisms.
Another candidate mechanism for inhibition of profi-
brotic effector functions of fibroblasts involves upregulation
of the tumor-suppressor phosphatase and tensin homologue
deleted on chromosome 10 (PTEN). The PTEN promoter
contains a PPRE, and PPARγ ligands upregulate PTEN ex-
fibroblast-myofibroblast differentiation and expression of α-
SMA and collagen in human and mouse lung fibroblasts
, while loss of PTEN activity contributes to the migra-
tory/invasive phenotype of lung fibroblasts isolated from IPF
patients . It has also been reported that PTEN levels are
decreased in the lung tissue of IPF patients, and that PTEN
knockout micearemore susceptibleto bleomycin-induced fi-
brosis . Interestingly, both 15d-PGJ2 and the RXR lig-
and 9-cis-retinoic acid inhibited transcription of the TGF-β1
gene via PTEN upregulation in mouse L929 fibroblasts ,
providing an additional mechanism by which PPARγ ligands
might interfere directly with the profibrotic effects of TGF-β.
One important consideration is that the effects of PPARγ
scriptional activation. PPARγ-dependent transcriptional re-
pression has been described in adipogensis, but not in my-
ofibroblast differentiation [93, 94]. Additionally, recent re-
ports have suggested that some of the biological effects of
15d-PGJ2are moderated by a PPARγ-independent mecha-
nism involving modification of protein thiols by an elec-
trophilic carbon on the imidazole ring of 15d-PGJ2[95, 96].
For example, the ability of troglitazone or 15d-PGJ2to in-
hibit proliferation of hepatic stellate cells was shown to be
PPARγ-independent , while 15d-PGJ2inhibts the pro-
liferation of human breast carcinoma cell lines by covalent
modification of the estrogen receptor DNA-binding domain
. We examined the PPARγ dependence of the antifi-
brotic effects of PPARγ ligands on human lung fibroblasts.
Neither the irreversible PPARγ antagonist GW9662 nor a
dominant-negative PPARγ mutant significantly blocked the
ability of 15d-PGJ2 to inhibit TGF-β-induced α-SMA ex-
pression, suggesting that this effect of 15d-PGJ2was largely
PPARγ-independent . However, the antifibrotic effects
of rosiglitizone were rescued significantly by the dominant-
negative PPARγ, suggesting that while rosiglitizone was less
was mostly dependent on PPARγ .
6. RETINOID X RECEPTOR
The PPARs must form heterodimers with the retinoid X re-
ceptor (RXR) in order to initiate gene transcription .
Therefore, it has been proposed that the anti-inflammatory
and antifibrotic functions of PPARs may be addressed or
enhanced by RXR ligands, predominantly the retinoic acids
acids (RA) reduced proliferation of HSCs and production
of collagen I. In addition, all-trans RAs inhibited the syn-
thesis of collagen I/II and fibronectin but did not affect
HSC proliferation . Levels of RXR-α and RXR-β were
decreased in the HSC of rats with cholestatic liver fibro-
sis . In addition, there were decreases in all-trans RA
and 9-cis-RA levels and RA binding to the retinoid receptor
response element (RARE) in fibrotic liver tissue. Similar
6 PPAR Research
findings have been demonstrated in glomerular mesangial
cells where 9-cis-RA induced the antifibrotic growth factor
HGF and inhibited TGF-β-stimulated induction of α-SMA
and fibronectin . Synergistic effects between RXR lig-
ands and PPAR ligands have not yet been reported in lung fi-
this is under investigation.
Although the role of the PPARs in fibrosing diseases has been
less well studied than their role in regulating inflammation,
a number of key results have emerged. PPARγ agonists in-
hibit the differentiation of lung fibroblasts to myofibroblasts
in vitro, and also inhibit airway remodeling and fibrosis in
animal models [77, 79]. PPARα agonists also attenuated fi-
brosis in the mouse bleomycin model, while PPARα knock-
out mice developed more severe disease .
Our understanding of the role of PPARs in lung fibro-
sis is hindered by the relative lack of experiments directly
involving the lung or lung cells. However, progress has also
been made toward determining the role of the PPARs in
fibrosing diseases of the liver, kidney, and pancreas. Hep-
atic stellate cells and pancreatic stellate cells differentiate to
myofibroblast-like cells under the same stimulus as lung fi-
broblasts, and this differentiation is inhibited by both nat-
ural and synthetic PPARγ ligands [83–85]. The TZD class of
ney fibrosis in rats and mice [44, 45, 72]. PPARα agonists,
including the fibrate drugs, have also shown promise in at-
tenuating liver, kidney, and cardiac fibrosis [40, 43, 45].
The mechanisms by which PPAR ligands alter fibrosis are
not well understood, but appear to involve multiple regula-
tory pathways (see Figure 3). Natural and synthetic PPARγ
agonists inhibit TGF-β-driven myofibroblast differentiation
and activation in hepatic stellate cells, kidney fibroblasts, and
lung fibroblasts. In human hepatic stellate cells, the PPARγ
agonist GW7845 inhibited Smad3 phosphorylation and nu-
clear translocation , while a similar result was seen with
15d-PGJ2in rat kidney fibroblasts . However, 15d-PGJ2
did not alter Smad2 phosphorylation in human lung fibrob-
lasts  or human renal mesangial cells, but instead upreg-
nism of action of PPARγ ligands varies depending on the cell
type and agonist used. A further complication is that PPARγ
agonists appear to have PPARγ-independent effects. Further
studies using pharmaceutical inhibitors of PPARγ or PPARγ
A very intriguing recent report found that 15d-PGJ2al-
tered transcriptional activity of the estrogen receptor by co-
valent modification of cysteine residues in its zinc finger
DNA-binding domain . Since cysteine is a ready target of
covalent modification by 15d-PGJ2[95, 96] and many tran-
scription factors use cysteine-rich zinc finger DNA-binding
PPARγ ligands can affect the regulation of cell differentiation
independently of PPARγ itself is via modification of other
involve downregulation of inflammation.
(2) PPARβ/δ plays a role in regulating the transition from in-
flammation to normal wound healing.
(3) PPARβ/δ agonists potentiate the antifibrotic activities of
(4) PPARγ ligands upregulate transcription of genes that op-
pose myofibroblast differentiation (PTEN).
(5) PPARγ ligands interfere with TGF-β signaling via the
Smad pathway in some cell types.
Figure 3: Key concepts in the regulation of fibrosis by PPARs.
There are less data available on the mechanism of action
of PPARα and β/δ agonists. Although PPARα agonists atten-
uate animal preclinical fibrosis models, studies of the direct
effect of PPARα ligands on myofibroblast activation have not
been reported. Treprostinil inhibition of lung fibroblast pro-
liferation is PPARβ/δ-dependent , and PPARβ/δ also ap-
pears to play a role in keratinocyte maturation and function
. It has been hypothesized that fibrosis is a consequence
ing an initial injury . This may provide the mechanistic
link between PPARα and β/δ and fibrosis. Rather than di-
rectly acting on fibroblasts and myofibroblasts, PPARα may
regulate inflammation, while PPARβ/δ regulates the transi-
tion from inflammation to wound healing [54, 105]. Thus,
PPARα and β/δ agonists may ameliorate fibrosis by altering
the initial inflammatory response and the transition to a fi-
brogenic milieu, respectively.
The relationship between the PPARs and fibrosis is likely
to be complex. As discussed above, PPARα and PPARγ are
involved in regulating both inflammation and fibrosis, and
some ligands have affinity for more than one PPAR. In ad-
dition, because RXR is the obligate dimerization partner for
all three PPARs, modulating RXR activity may have multiple
overlapping or even conflicting effects. A number of useful
tools exist to study these relationships, including highly spe-
cific synthetic agonists and antagonists, dominant negative
expression constructs, and germline and conditional gene
knockouts. Each of these approaches has potential advan-
tages and drawbacks. In particular, genetic ablation of PPAR
genes will eliminate their function from both inflammatory
and repair processes, making it difficult to determine their
role in each process independently. This problem can be ad-
dressed by using multiple complimentary approaches to ex-
amine PPAR function in both normal and abnormal wound
repair and fibrosis.
It must be emphasized that important classes of PPARα
(the fibrate drugs) and PPARγ (TZDs) agonists are currently
available in the clinic. Although the frequency of lung fi-
brosis in the general population is not high, it may be pos-
sible to perform retrospective studies of long-term users of
TZDs and fibrates to determine whether these drugs reduce
the incidence or severity of lung fibrosis and other fibrosing
diseases. More importantly, the clinical availability of these
Heather F. Lakatos et al.7
drugs means that significant results from animal studies of
fibrosis models may be rapidly applied in the clinical set-
ting. Recent advances in drug delivery by inhalation may al-
low delivery of antifibrotic PPAR agonists directly to the site
of fibrosis (as has already been demonstrated with the use
of ciglitazone in a mouse model of airway remodeling ),
achieving higher effective doses at the target site with lower
systemic side effects. As most forms of lung fibrosis are re-
fractory to current treatment, the rapid translation of basic
research to bedside practice holds great promise for a patient
population suffering from a largely untreatable disease.
This work was supported in part by HL-04492, HL-75432l,
the James P. Wilmot Foundation, The National Institute of
Environmental Health Sciences Center Grant ES-01247, Na-
tional Institute of Environmental Health Sciences Training
Grant ES-07026, and The Connor Fund. R. P. Phipps was
supported by DE-011390, HL-078603, and HL-086367. T. H.
Thatcher was supported in part by a postdoctoral fellowship
from Philip Morris, USA.
 V. J. Thannickal, G. B. Toews, E. S. White, J. P. Lynch III, and
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