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The Proceedings of the American Thoracic Society 2:226-231 (2005)
© 2005 The American Thoracic Society

Peroxisome Proliferator-activated Receptor-{gamma} as a Regulator of Lung Inflammation and Repair

Theodore J. Standiford, Venkateshwar G. Keshamouni and Raju C. Reddy

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Theodore J. Standiford, M.D., 6301 MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109. E-mail: tstandif{at}umich.edu

ABSTRACT

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that regulate the expression of genes involved in a variety of biological processes, including lipid metabolism and insulin sensitivity. Members of the PPAR family—in particular, PPAR-{gamma}—have more recently been shown to broadly regulate inflammatory and reparative responses. PPAR-{gamma} is expressed in both alveolar macrophages and neutrophils, and the ligand-dependent activation of this receptor results in suppression of leukocyte effector responses, including cytokine production, the elaboration of reactive oxygen and nitrogen species, and migratory responses. In addition to antiinflammatory effects, PPAR-{gamma} regulates diverse processes in lung stromal/parenchymal cells, including cell growth, differentiation, and apoptosis. Studies examining in vivo effects of PPAR-{gamma} have produced complex and at times conflicting results. However, evidence to date generally suggests that PPAR-{gamma} functions to dampen inflammation and injury in various animal models of acute lung injury. PPAR-{gamma} may also play an important role in other inflammatory/immune lung diseases, including ischemia-reperfusion injury, allergic airway inflammation, and cancer. The role of PPAR-{gamma} in human lung diseases, including acute lung injury, requires further study.

Key Words: transcriptional factors • ARDS • gene regulation

Acute lung injury (ALI) and the acute respiratory distress syndrome are diseases characterized by the excessive release of inflammatory mediators and injury to the alveolar–capillary membrane, which can promote a reparative response distinguished by fibroproliferation (1). The extent of lung injury and subsequent repair is dependent on sufficient control of lung inflammation, the ability to regenerate the injured alveolar epithelium, and an appropriately regulated mesenchymal cell response (1–3). Mechanisms controlling the magnitude of lung injury and subsequent repair have been incompletely defined. Data from our laboratory and the laboratories of others suggest that members of the peroxisome proliferator-activated receptor (PPAR) family of nuclear transcription factors may play a key role in regulating inflammatory and reparative responses in the lung in ALI.

PPARs: OVERVIEW

PPARs are members of the nuclear hormone receptor superfamily that were initially characterized as molecules that mediated the proliferation of peroxisomes in rodent liver parenchymal cells in response to the hypolipidemic drug clofibrate (4). Subsequently, PPARs have been shown to regulate the expression of genes involved in a variety of biological processes, including lipid metabolism and insulin sensitivity (5, 6). Three isotypes of PPAR exist, PPAR-{alpha}, PPAR-{delta}, and PPAR-{gamma}, which are encoded by three separate genes and display distinctly different tissue distributions and function. PPAR-{gamma}, like other PPAR isotypes, exists as a heterodimer complexed with the retinoid X receptor and several corepressor molecules that tonically suppress PPAR activity (Figure 1) (7). In the presence of PPAR ligands, corepressor molecules are shed, followed by association of coactivator proteins, binding to specific PPAR-response elements, and transcription of target genes (5–7). PPAR-{gamma} is highly expressed in adipose tissue, and plays a fundamental role in adipocyte differentiation (8). In addition to its role in adipogenesis, PPAR-{gamma} serves as an important transcriptional regulator of genes involved in glucose and lipid metabolism. More recently, various leukocyte populations, including monocytes/macrophages, lymphocytes, and dendritic cells, have also been shown to express PPAR-{gamma}, suggesting a role for this molecule in the regulation of immune responses (9). Low levels of PPAR-{gamma} are present in bone marrow macrophages and circulating blood monocytes. In contrast, abundant expression is found in macrophages obtained from thioglycollate-elicited peritonitis, suggesting that factors produced during inflammatory responses stimulate PPAR-{gamma} expression (10, 11).



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  		Figure 1. Overview of ligand-mediated peroxisome proliferator-activated receptor (PPAR)-{gamma} activation. In its unactivated state, PPAR-{gamma} exists as a heterodimer complexed with the retinoid X receptor and corepressor molecules, including nuclear receptor corepressor (NCoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT). In the presence of PPAR ligands, corepressor molecules are shed, followed by association of coactivator molecules, such as steroid receptor co-activator 1 (SRC1) and cAMP-response element-binding protein (CBP)/p300. Binding of this complex to specific PPAR-response elements (PPRE) results in transcription of target genes (as indicated by arrow). Modified by permission from Reference 9.

 
Several structurally distinct molecules bind to and activate PPAR-{gamma}. A partial list of PPAR-{gamma} ligands and relative potency of PPAR-{gamma} agonist effects is shown in Table 1 (12–19) For instance, the thiazolidinedione compounds (TZDs), certain nonsteroidal antiinflammatory drugs, and a number of naturally occurring compounds, including polyunsaturated fatty acids, prostaglandin D2 (PGD2) and its metabolite 15-deoxy-{Delta}12,14 prostaglandin J2 (15d-PGJ2), and the 12/15 lipoxygenase products 15-hydroxyeicosatetraenoic acid (15-HETE) and 13-hydroxyoctadecadienoic acid, bind to PPAR-{gamma} and stimulate transcription of target genes (12–19). Importantly, ligand activation of PPAR-{gamma} in monocytes has been shown to exert potent suppressive effects on proinflammatory mediator release, including the release of cytokines (e.g. tumor necrosis factor {alpha} [TNF-{alpha}], interleukin [IL] 1, and IL-6), nitric oxide, and matrix metalloproteinases (10, 11, 20, 21). The suppressive effects of PPAR-{gamma} are complex but have been shown to be partially mediated through antagonism of the transcription factors nuclear factor-{kappa}B (NF-{kappa}B), activator protein, and Stat-1 (10, 11, 20, 22–25). For example, ligand-mediated activation of PPAR-{gamma} can inhibit signal transduction by multiple mechanisms, including the following: (1) consumption of coactivator molecules required for NF-{kappa}B activation, (2) direct binding and shuttling of NF-{kappa}B subunits (e.g., Rel A/p65) from the nucleus, (3) regulation of inhibitor-{kappa}B expression/phosphorylation, and (4) inhibition of upstream kinases required for mitogen-activated protein kinase (MAPK) activation (20–24). The PPAR-{gamma}–mediated antiinflammatory effects are not restricted to monocytes, as treatment with PPAR-{gamma} agonists results in inhibition of cytokine and chemokine production from various stromal/parenchymal cell populations. Additional studies suggest that PPAR-{gamma} may also play a critical role in regulating cell growth, differentiation, apoptosis, and angiogenesis (26–30).


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  		TABLE 1. Partial list of synthetic and endogenous ppar-{gamma} ligands

 
PPAR-{gamma} research has been limited by several significant obstacles. First, mice that are genetically deficient in PPAR-{gamma} die in utero, although heterozygous PPAR-{gamma}–deficient mice have been generated that display reduced PPAR-{gamma} activity relative to wild-type animals (23). Also, various ligands used to activate PPAR-{gamma} can exert a multitude of biological effects that are mediated through both PPAR-{gamma}–dependent PPAR-{gamma}–independent mechanisms. This is particular true for a number of naturally occurring eicosanoid ligands, but can also be seen with various TZD compounds (31, 32). Last, the putative endogenous ligand for PPAR-{gamma} remains unclear. Despite these limitations, existing experimental data suggest that PPAR-{gamma} functions as an important antiinflammatory molecule in vivo. Specifically, gut ischemia-reperfusion injury in mice results in significant induction of PPAR-{gamma} in colon, small bowel, and liver. Interestingly, a reduction in ischemia-reperfusion injury was observed in animals treated with a PPAR-{gamma} activator (BRL-49653), whereas greater intestinal injury was observed in heterozygous PPAR-{gamma}–deficient (+/–) mice, as compared with wild-type animals (33). Enhanced PPAR-{gamma} expression has also been observed in experimental models of inflammatory colitis and adjuvant induced arthritis, and treatment with endogenous or exogenous PPAR-{gamma} ligands suppressed inflammation in these models (34, 35). More recently, treatment of mice with synthetic PPAR-{gamma} agonists was shown to decrease mortality in an endotoxemia model and reduce multiorgan failure and mortality in a murine model of zymosan-induced shock (36, 37). Improvements in clinical outcomes in response to zymosan were associated with reductions in organ-specific neutrophil influx, TNF-{alpha} production, and the elaboration of reactive nitrogen species. Although these studies suggest potent antiinflammatory effects of PPAR-{gamma} both in vitro and in vivo, little is known regarding the contribution of PPAR-{gamma} to the regulation of inflammation or injury in the lung.

PPAR-{gamma} AS A REGULATOR OF LUNG INFLAMMATORY RESPONSES

PPAR-{gamma} in the Regulation of Alveolar Macrophage Function
The generation of inflammation in the lung is dependent on the coordinated and tightly regulated expression of cytokines and chemokines, eicosanoids, reactive oxygen and nitrogen species, and adhesion molecules. The alveolar macrophage (AM) is a rich cellular source of a variety of bioactive molecules, and as such, these cells represent critical components of both the afferent and efferent limbs of lung inflammatory responses. To assess the role of PPAR-{gamma} in regulating AM effector cell responses, we first determined if murine AMs expressed PPAR-{gamma}. Interestingly, mouse AMs expressed very high levels of PPAR-{gamma} mRNA (predominantly the PPAR-{gamma}2 isotype) and protein, and the expression of PPAR-{gamma} was substantially upregulated by the antiinflammatory cytokine IL-4 (38). Treatment of AMs with PPAR-{gamma} agonists (selected TZDs or the endogenous ligand 15d-PGJ2) resulted in suppression of LPS-induced cytokine production (TNF-{alpha} and especially IL-12), inducible nitric oxide synthase expression, and oxidative burst. Likewise, PPAR-{gamma} has been shown to be strongly expressed in human AMs, and incubation of these cells with PPAR-{gamma} agonists significantly decreased the expression of TNF-{alpha} while enhancing the cell surface expression of CD36, a scavenger receptor that mediates the phagocytosis and clearance of apoptotic neutrophils within the airspace (39). Collectively, these findings indicate an important antiinflammatory role of PPAR-{gamma} similar to that observed in other macrophage populations. A schematic of PPAR-{gamma} effects on AMs is shown in Figure 2.



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  		Figure 2. Overview of regulation and effects of PPAR-{gamma} activation on alveolar macrophage (AM) effector cell functions. PPAR-{gamma} expression is enhanced by interleukin (IL) 4, leading to regulation of several effector cell functions, including NADPH oxidase activity and subsequent respiratory burst, inducible nitric oxide synthase (iNOS) expression, cytokine production, matrix metalloproteinase (MMP) elaboration, and scavenger receptor (CD36) expression. TNF = tumor necrosis factor.

 
PPAR-{gamma} as an Immunomodulator of Inflammation in Experimental Models of ALI
The role of PPAR-{gamma} in regulating pulmonary inflammation in the setting of ALI has not been defined. To better understand the contribution of PPAR-{gamma} in ALI, we used a murine fluorescein isothiocyanate (FITC)–induced lung injury model. In this model, the intratracheal administration of FITC results in early neutrophil-predominant intraalveolar inflammation and high-permeability pulmonary edema, followed by the development of patchy fibrosis, maximum at 21 to 28 d post–FITC challenge (40). The intratracheal administration of FITC to C57Bl/6 mice resulted in a considerable time-dependent increase in PPAR-{gamma} expression in both lung macrophages and whole lung. Mice were then treated with the synthetic PPAR-{gamma} agonist pioglitazone or vehicle by oral gavage daily for 5 d, then challenged with intratracheal FITC. Treatment of control mice with FITC resulted in marked alveolar inflammation, which was neutrophil predominant and maximal at 3 d postadministration. FITC also induced considerable lung alveolar protein leak, which was maximal between 3 and 7 d postinjury. Interestingly, pretreatment of animals with pioglitazone substantially decreased alveolar inflammation, with an approximately 50% reduction in bronchoalveolar lavage (BAL) neutrophils at 3 d after FITC challenge. Somewhat surprisingly, this decrease in pulmonary inflammation was not associated with changes in the expression of inflammatory cytokines (TNF-{alpha}, macrophage inflammatory protein-2, KC, IL-12, or IFN-{gamma}) in either BAL fluid or whole lung homogenates. Likewise, we did not observe significant alterations in lung permeability in pioglitazone-treated mice challenged with FITC, as compared with similarly treated vehicle control animals. One possible mechanism by which PPAR-{gamma} suppresses inflammation in the absence of changes in cytokine expression is by directly influencing the ability of neutrophils (and possibly other leukocyte populations) to migrate in response to endogenous chemoattractants (as discussed in more detail below). Similar suppressive effects of pioglitazone on the development of alveolar inflammation were observed in a bleomycin-induced lung injury model. In contrast to these findings, Inoue and associates (41) found that pretreatment of mice with 15d-PGJ2 failed to suppress pulmonary inflammation induced by intratracheal LPS administration. In fact, at the highest concentrations (1 mg/kg), 15d-PGJ2 paradoxically enhanced LPS-induced alveolar inflammation, pulmonary edema, and inflammatory cytokine expression. Factors contributing to these disparate results are as yet unknown, but perhaps might be attributed to PPAR-independent effects of specific ligands or differences in the model systems used.

PPAR-{gamma} in the Regulation of Neutrophil Function
Given the appreciable suppressive effects of PPAR-{gamma} agonists on the influx of neutrophils in several animal model systems, including the intratracheal FITC challenge model, we next determined the contribution of PPAR-{gamma} to regulation of neutrophil function. In initial studies, we observed that both human and mouse neutrophils express PPAR-{gamma} mRNA and protein, and the expression of PPAR-{gamma} was induced by either TNF-{alpha} or IL-4 (unpublished data). Importantly, the incubation of resting human neutrophils with PPAR-{gamma} agonists (15d-PGJ2 or troglitazone) resulted in the dose-dependent suppression of neutrophil chemotactic responses to either formylmethionylleucylphenylalanine or IL-8 in vitro, which occurred in association with reductions of extracellular regulated kinase 1/2, but not p38 MAPK phosphorylation. Our findings are consistent with previous studies demonstrating direct suppressive effects of PPAR-{gamma} agonists on migration of other immune cells, including monocytes and eosinophils (42, 43). We also observed that incubation with PPAR-{gamma} ligands inhibited the ability of neutrophils to produce inflammatory cytokines (IL-12, TNF-{alpha}, IL-8) in response to LPS. The suppressive effects of PPAR-{gamma} agonists on neutrophil chemotactic responses and cytokine production were not attributable to cellular toxicity or induction of apoptosis. Collectively, these data indicate that PPAR-{gamma} exerts important direct inhibitory effects on neutrophil function, which may contribute to attenuation of neutrophil accumulation observed in vivo.

Effect of PPAR-{gamma} on Regulation of Lung Structural Cells That Contribute to Lung Injury and Repair in ALI
Alveolar epithelial cells.
Alveolar epithelial cells have traditionally been viewed simply as cellular targets of early events that occur in the setting of ALI. However, alveolar epithelial cells clearly contribute to both the initiation and perpetuation of intraalveolar inflammation, fibrinolysis, and fibroproliferation. Moreover, resolution of high-permeability edema and appropriate control of the lung reparative process is dependent on the orderly reconstitution of an intact alveolar epithelium (44). Given the discordant effects of PPAR-{gamma} agonists on lung inflammation and permeability changes in FITC-induced lung injury, we next examined direct effects of PPAR-{gamma} activation on alveolar epithelial cell function. PPAR-{gamma} is constitutively expressed in several transformed alveolar epithelial cell lines, including human A549 and murine MLE-15 cells, and its expression is substantially enhanced in A549 cells by IL-4 (45). Primary alveolar epithelial cells isolated from mice or rats also express PPAR-{gamma}, although its expression is not as readily inducible as that observed in lung transformed cell lines (T. J. S., unpublished observations). Similar to effects on various leukocyte populations, treatment of A549 alveolar type II–like epithelial cells with 15d-PGJ2 or TZDs, or the forced expression of a constitutively active PPAR-{gamma} gene, resulted in suppression of NF-{kappa}B transcriptional activity and decreased inflammatory cytokine and chemokine production from these cells (27). However, incubation with PPAR-{gamma} ligands also resulted in significant suppression of proliferative responses and growth arrest in the G0G1 phase of the cell cycle (26). Impaired proliferative responses occurred in association with prominent inhibition of cell cycle regulators cyclin D and cyclin E. The growth inhibitory effects of PPAR-{gamma} were not due to induction of apoptosis, as we observed minimal evidence of apoptosis or changes in caspase expression in agonist-treated cells. Likewise, treatment of murine alveolar epithelial cells (MLE-15) with PPAR-{gamma} ligands resulted in similar growth suppressive effects. Interestingly, culturing MLE-15 alveolar epithelial cells in hyperoxic conditions (95% O2) resulted in more pronounced growth inhibitory effects of PPAR-{gamma} agonists, as compared with cells cultured under normoxic conditions. These studies would suggest that the beneficial antiinflammatory properties of PPAR-{gamma} in ALI may be partially offset by the growth inhibitory effects on alveolar epithelial cells, and this antiproliferative response may be potentiated by factors present within the lung microenvironment (e.g., hyperoxia).

Pulmonary fibroblasts.
Lung injury, and in particular damage to alveolar epithelium, results in activation of fibroblasts that reside in the lung interstitium and promotes the process of fibroproliferation. A hallmark of fibroproliferation in response to injury is accumulation of stromal cells, including fibroblasts, as well as the differentiation of fibroblasts into myofibroblasts (46). Myofibroblasts are of particular relevance to fibroproliferative lung disease, as these cells display a marked increase in their capacity to synthesize extracellular matrix components and express contractile elements, including {alpha}-smooth muscle actin (47). Previous studies indicate that treatment with either 15d-PGJ2 or synthetic ligands (troglitazone or pioglitazone) inhibit {alpha}-smooth muscle actin and type 1 collagen synthesis by hepatic or pancreatic stellate cells in vitro (48, 49), and mitigate the development of carbon tetrachloride–induced hepatic fibrosis in vivo (50). Importantly, we have found that incubation of human fetal lung fibroblasts (IMR90) with PPAR-{gamma} agonists inhibits transforming growth factor ß (TGF-ß)–stimulated proliferative responses and cyclin D expression (R. C. R., unpublished observations). Furthermore, PPAR-{gamma} agonists blocked TGF-ß–induced fibroblast-to-myofibroblast transdifferentiation, as manifested by reductions in collagen production and decreases in {alpha}-smooth muscle actin expression. Similarly, Burgess and colleagues (51) have recently reported that 15d-PJG2, ciglitazone, and pioglitazone can inhibit TGF-ß–driven differentiation of pulmonary fibroblasts into myofibroblasts, which occurs through both PPAR-{gamma}–dependent and PPAR-{gamma}–independent mechanisms. In total, these data suggest that PPAR-{gamma} serves as a negative regulator of fibroblast proliferation and differentiation, functions that might be of considerable relevance to events that occur during fibroproliferation in ALI.

PPAR-{gamma}/PPAR-{gamma} LIGAND EXPRESSION IN PATIENTS WITH ALI

Our laboratory has begun to explore the role of PPAR-{gamma} as a regulator of inflammation and repair in patients with ALI. We have found enhanced expression of PPAR-{gamma} mRNA and PPAR-{gamma} transcriptional activity in AMs recovered from patients with ALI, as compared with AMs obtained from healthy control subjects. Furthermore, we have isolated mesenchymal cells from the BAL fluid of patients with ALI that, when cultured ex vivo, express several phenotypic markers of differentiated fibroblasts, including collagen, proyl-4-hydroxylase, and {alpha}-smooth muscle actin (Victor Thannickal, unpublished observations). Interestingly, these cells express PPAR-{gamma}, and incubation of these alveolar mesenchymal cells with troglitazone results in the time-dependent suppression of cell proliferation. Finally, AMs recovered from patients with ALI expressed considerable quantities of several endogenous PPAR-{gamma} ligands, including PGD2 and 15-HETE. Elevated levels of PGD2 and 15-HETE can also be found in lipid-extracted BAL fluid recovered from patients with ALI (~ 2.5- and > 50-fold greater than levels in control BAL fluid, respectively). Although it has been reported that 15d-PGJ2 can be detected in inflammatory tissues and produced in large quantities by activated macrophages (52), these findings have not been confirmed by others. In a related study, we have observed increased expression of PPAR-{gamma} mRNA in peripheral blood monocytes and neutrophils isolated from patients with sepsis with or without ALI, suggesting that PPAR-{gamma} may contribute to the phenomenon of leukocyte deactivation that occurs during the septic response.

ROLE OF PPAR-{gamma} IN OTHER PATHOLOGIC PROCESSES IN THE LUNG

Ischemia-Reperfusion Injury
Lung ischemia-reperfusion injury is a major cause of early graft failure in lung transplantation. This insult is characterized by proinflammatory cytokine expression, generation of reactive oxygen and nitrogen species, and the accumulation of neutrophils within the lung interstitium. Recent data suggest that PPAR-{gamma} functions to dampen injury in the setting of lung ischemia-reperfusion. For instance, pretreatment with intraperitoneal pioglitazone (10 mg/kg) decreased lung vascular permeability, oxidant activity, neutrophil influx, and cytokine production (TNF-{alpha} and cytokine-induced neutrophil chemoattractant-1 protein) in a rat ischemia-reperfusion model (53). Similarly, pretreatment with 15d-PGJ2 or troglitazone, but not the PPAR-{alpha} agonist bezafibrate, decreased inflammatory cytokine and chemokine expression and pulmonary leukostasis, while improving oxygenation and survival in a mouse lung ischemia-reperfusion injury model (54). Protection in this model was attributable, in part, to suppression of early growth response gene-1, which is a major transcriptional regulator of ischemia-induced inflammation and injury.

Allergic Airway Inflammation
Asthma is characterized by airway hyperresponsiveness, accumulation of eosinophils and other inflammatory cells, airway remodeling, and increased IgE production. PPAR-{gamma} has recently been shown to be a key regulator of the allergic airway inflammation (55–57). For example, in a murine allergic asthma model induced by ovalbumin, aerosolized delivery of ciglitazone decreased antigen-induced hyperresponsiveness, airway inflammation, BAL eosinophilia, type 2 cytokine production, and antigen-specific IgE production (55, 56). Moreover, in vitro incubation of eosinophils with selected PPAR-{gamma} agonists decreased chemotactic responses and antibody-dependent cellular cytotoxicity. Enhanced PPAR-{gamma} expression has been detected in the airway epithelium, bronchial submucosa, and smooth muscle of airway tissue obtained from patients with asthma (57), supporting the notion that PPAR-{gamma} might participate in the process of airway remodeling that often occurs in this patient population.

Lung Tumor Growth and Progression
Cancer cells have been shown to de-differentiate before acquiring a proliferative and antiapoptotic phenotype. Taking into account the differentiation-promoting effects of PPAR-{gamma}, agonists of this receptor have been used therapeutically in a variety of tumor cell models. Of note, treatment with PPAR-{gamma} agonists can induce differentiation and slow or arrest growth of several tumor cell types, including human breast, prostate, and colon cancers (58–60). In addition, somatic mutations in the gene encoding PPAR-{gamma} have been linked to the sporadic development of colorectal carcinomas (61). We have shown that treatment of non–small cell lung cancer cell lines (A549, H520) in vitro with troglitazone induced tumor cell differentiation and growth arrest (26). Moreover, the daily oral administration of either troglitazone or pioglitazone to severe combined immunodeficient mice decreased primary tumor growth and pulmonary metastases in an A549 tumor xenograph model. In addition to direct effects on tumor growth, PPAR-{gamma} agonists also inhibited the release of angiogenic cytokines and activity from A549 cells both in vitro and in vivo (27). We are currently investigating whether PPAR-{gamma} can function to suppress spontaneous tumor development using a transgenic mouse model in which the oncogene {kappa}-ras is expressed (V. G. K., unpublished observations). Taken together, these data suggest that PPAR-{gamma} may represent an attractive therapeutic target in both the prevention and treatment of lung cancer.

Alveolar Proteinosis
Pulmonary alveolar proteinosis is a disease characterized by impaired catabolism of surfactant by AMs and/or alveolar epithelial cells, resulting in accumulation of surfactant within the airspace. Interestingly, AMs recovered from patients with pulmonary alveolar proteinosis have considerably reduced levels of PPAR-{gamma} compared with healthy control subjects (62). The reason for reduced PPAR-{gamma} expression in these cells is unknown. However, pulmonary alveolar proteinosis has been causally linked to antibody-mediated reductions in granulocyte-macrophage colony–stimulating factor. Furthermore, granulocyte-macrophage colony–stimulating factor is a potent inducer of PPAR-{gamma}, and treatment with exogenous granulocyte-macrophage colony–stimulating factor can reverse the relative deficiency of PPAR-{gamma} in AMs from patients with pulmonary alveolar proteinosis. Despite the intriguing association between reduced PPAR-{gamma} expression and altered surfactant metabolism, direct evidence that implicates PPAR-{gamma} in the regulation of surfactant production is lacking. It should also be noted that PPAR-{gamma} could exert effects that negatively impact surfactant production and/or function, as cell-differentiating effects of PPAR-{gamma} ligands can reduce the expression of selected surfactant proteins from alveolar type II–like cell lines (26).

CONCLUSIONS

Cumulative experimental evidence indicates that PPAR-{gamma} is a transcriptional factor with diverse biological properties. PPAR-{gamma} appears to be a key molecule in controlling the magnitude of inflammation in ALI. Furthermore, direct effects of PPAR-{gamma} on mesenchymal cell proliferation, differentiation and synthetic function, and the process of angiogenesis might be of particular relevance to the fibroproliferative response in ALI. However, beneficial effects of PPAR-{gamma} in ALI may be counterbalanced by antiproliferative (and perhaps apoptotic) effects on the alveolar epithelial cells, limiting the ability of these cells to reconstitute an intact epithelial surface in response to injury. Effects on multiple and at times opposing processes are not unique to PPAR-{gamma}, but illustrate a common limitation when proximal signaling molecules with broad-reaching and pleotropic effects are targeted. Studies using PPAR-{gamma} ligands to define PPAR-{gamma}–specific effects should be interpreted with caution. The recent generation of conditional PPAR-{gamma}–deficient mice represents a major advance in PPAR-{gamma} research.

FOOTNOTES

Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form January 28, 2005; accepted in final form May 2, 2005)

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