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Peroxisome Proliferator–Active Receptor

A Legitimate Target to Control Pulmonary Inflammation?

Program in Cell Biology Department of Pediatrics National Jewish Medical and Research Center Denver, Colorado

The mechanisms underlying the evolution and resolution of pulmonary inflammation have been studied in great depth in the past two decades. In the "normal" lung, the airway and alveolar surfaces are continuously exposed to environmental particulates, allergens, and sub-threshold numbers of bacteria. The lung, however, does not become inflamed or infected, in part because alveolar and airway macrophages express a number of anti-inflammatory molecules that tonically suppress pulmonary inflammation (as reviewed by [1]). On encountering threshold or higher levels of pro-inflammatory or infectious agents, resident alveolar macrophages and epithelial cells respond by producing chemokines, cytokines, complement fragments, and lipids that promote the transmigration of neutrophils from the pulmonary circulation into the airspaces. The neutrophils then perform a number of functions including killing and removing bacteria, and initiating tissue remodeling by phagocytosing dead and dying epithelial cells (2). During the next few days, monocytes are also recruited to the airspaces where they rapidly differentiate into macrophages to supplement the resident alveolar macrophage pool. Although it was initially thought that the wave of macrophage accumulation served to complete the clean-up of damaged tissue and to kill any remaining bacteria, it has become clear that macrophages also play an active role in the resolution of pulmonary inflammation through their ability to engulf neutrophils undergoing programmed cell death (3). This latter event serves to eliminate neutrophils from the airspaces thereby preventing them from causing further damage to the alveolar epithelium. It also provides an instructive signal to macrophages to start producing active transforming growth factor-ß (4), an anti-inflammatory cytokine that downregulates the production of pro-inflammatory cytokines and plays a vital role in the regulation of connective tissue matrix repair.

Recent studies provide further insights into the mechanisms that may contribute to both the basal suppression of pulmonary inflammation in the "normal" lung and to the resolution of acute pulmonary inflammation. Peroxisome proliferator–activated receptors (PPARs) are a family of a ligand-activated transcription factors that regulate diverse aspects of lipid metabolism and inflammation. Of the known isoforms, PPAR is expressed by macrophages and its activity as a transcription factor is increased by intracellular interaction with ligands that include 15d-PGJ₂ and troglitazone, a drug that had shown promise in the treatment of type II diabetes. Activation of PPAR by these ligands inhibits the production by macrophages of several pro-inflammatory cytokines, recapitulating the effects of transforming growth factor-ß. Until recently, however, little was known about the relationship of these findings to pulmonary inflammation. New insights into this question are revealed in work reported by Asada and colleagues (5) in this issue of the Journal (pp. 195–200). Their study demonstrates that while PPAR is absent from peripheral blood monocytes, it is abundantly expressed by alveolar macrophages. Moreover, in seeking to define the functional consequences of these differences in PPAR expression, the authors determined the effects of 15d-PGJ₂ and troglitazone on endotoxin-induced tumor necrosis factor- production and CD36 expression by human alveolar macrophages and blood monocytes. The authors found that exposure to PPAR ligands inhibited the production of tumor necrosis factor- and augmented the expression of CD36 by alveolar macrophages, but were without effect on blood monocytes. These findings are significant since CD36 recognizes a variety of molecules expressed on the surfaces of apoptotic neutrophils including vitronectin (6) and phosphatidylserine (7). Furthermore, CD36 is one of several macrophage receptors that are involved in "tethering" apoptotic neutrophils to macrophages before engulfment (7). Consistent with this concept, Asada and coworkers (5) also found that incubation of alveolar macrophages with PPAR agonists augmented the engulfment of apoptotic neutrophils in a CD36-dependent fashion.

In a pair of recently published articles, Culver and coworkers (8) and Bonfield and coworkers (9) also report that alveolar macrophages from healthy individuals express PPAR. Alveolar macrophages from patients with sarcoidosis or pulmonary alveolar proteinosis, however, were found to be deficient in PPAR activity, suggesting that the expression and/or activity of PPAR is downregulated during active pulmonary inflammation. Moreover, macrophages from patients with pulmonary alveolar proteinosis and sarcoidosis exhibited reduced expression of CD36 and increased nuclear factor-B activity, respectively. These findings combined with the findings of Asada and coworkers (5) suggest that in the absence of pulmonary inflammation, PPAR is expressed by alveolar macrophages and can respond to ligand binding by instructing a gene expression pattern consistent with the ability of alveolar macrophages to suppress basal pulmonary inflammation. In addition, this pattern of gene expression is also similar to that exhibited by macrophages during the resolution of inflammation. In the inflamed lung, however, the expression of PPAR by macrophages is downregulated. Could this be related to the fact that blood monocytes supplement the alveolar macrophage pool during pulmonary inflammation? Or do other mechanisms suppress PPAR expression during the inflammatory response? Answers to these questions remain to be determined.

Collectively, these studies raise a number of interesting issues regarding the possible role of PPAR in pulmonary inflammation. First, deletion of the PPAR gene in mice is lethal. Akiyama and coworkers (10), however, have created mice in which PPAR has been conditionally deleted in macrophages. These mice may therefore provide insights into the role of PPAR in suppressing basal pulmonary inflammation as well as in the resolution of induced pulmonary inflammation. Second, while 15d-PGJ₂ is a naturally occurring PPAR ligand, little is known about its source. Indeed, recent studies in which 15d-PGJ₂ levels were measured in cell culture supernatants and in synovial fluid samples from patients with rheumatoid arthritis have drawn into question the role of this molecule in stimulating PPAR activity under both physiologic or even pathologic conditions (11). Thus, further studies are needed to identify physiologic ligands of PPAR and their sources. Finally, thiazolidinedione drugs have been used to stimulate PPAR activity in patients with type II diabetes, atherosclerosis, and inflammatory bowel disease. Because PPAR may be a legitimate target to downregulate inflammation in the lung, perhaps this class of drug may also hold the promise of being useful in the treatment of acute and chronic pulmonary inflammation.

FOOTNOTES

Conflict of Interest Statement: D.W.H.R. has no declared conflict of interest.

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