Regulation of Peroxisome Proliferator-activated Receptor γ Expression in Human Asthmatic Airways

Abstract

Airway inflammation and alterations in cellular turnover are histopathologic features of asthma. We show that the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear hormone receptor involved in cell activation, differentiation, proliferation, and/or apoptosis, is augmented in the bronchial submucosa, the airway epithelium, and the smooth muscle of steroid-untreated asthmatics, as compared with control subjects. This is associated with enhanced proliferation and apoptosis of airway epithelial and submucosal cells, as assessed by the immunodetection of the nuclear antigen Ki67, and of the cleaved form of caspase-3, respectively, and with signs of airway remodeling, including thickness of the subepithelial membrane (SBM) and collagen deposition. PPAR gamma expression in the epithelium correlates positively with SBM thickening and collagen deposition, whereas PPAR gamma expressing cells in the submucosa relate both to SBM thickening and to the number of proliferating cells. The intensity of PPAR gamma expression in the bronchial submucosa, the airway epithelium, and the smooth muscle is negatively related to FEV(1) values. Inhaled steroids alone, or associated with oral steroids, downregulate PPAR gamma expression in all the compartments, cell proliferation, SBM thickness, and collagen deposition, whereas they increase apoptotic cell numbers in the epithelium and the submucosa. Our findings have demonstrated that PPAR gamma (1) is a new indicator of airway inflammation and remodeling in asthma; (2) may be involved in extracellular matrix remodeling and submucosal cell proliferation; (3) is a target for steroid therapy.

Peroxisome proliferator–activated receptor γ is expressed in airways and inhibits features of airway remodeling in a mouse asthma model☆

“…32 In our animal model of asthma, PPAR-c expression in the lung remained undetectable by means of immunohistochemistry and was only evidenced as a very faint band by means of Western blotting in the absence of antigen sensitization. However, consistent with the study performed in human subjects, 32 expression levels were greatly increased in inflammatory lung tissue on antigen sensitization and challenge and hence were reduced after nebulization of a PPAR-c agonist, which decreases inflammation.…”

“…32 This expression is increased in biopsy specimens from asthmatic patients compared with those from healthy donors and is positively correlated with basement membrane thickness and negatively correlated with lung functions. 32 In our animal model of asthma, PPAR-c expression in the lung remained undetectable by means of immunohistochemistry and was only evidenced as a very faint band by means of Western blotting in the absence of antigen sensitization.…”

Peroxisome Proliferator‐Activated Receptors: Potential Therapeutic Targets in Lung Disease?

“…62 For PPARg, gene expression is increased in numerous cell types by multiple factors, including cytokines (TNF-a, IL-1b, IL-4), 7 statins, 63 butyrate, 24 cross-linking of IgE receptors on mast cells, 36 and the anti-inflammatory flavinoid amentoflavone. 64 Moreover, PPARg is strikingly upregulated upon differentiation of monocytes to macrophages, 7 and is elevated in asthma 65,66 and in cancer cells. 12 In contrast to other tissues, however, PPARg is downregulated in adipose tissue by proinflammatory cytokines (TNF-a, IL-1b, and IL-6), 7 indicating that, like PPARa, regulation of PPARg expression can be cell typespecific.…”

“…PPARg is also downregulated by IFN-g and LPS in macrophages, 45 and by steroids in the lung. 66 Far fewer studies have examined the regulation of PPARb/d gene expression. However, the theme of celltype specific regulation also applies, as TNF-a upregulates PPARb/d in keratinocytes 67 and downregulates it in oligodendrocytes.…”

“…99 In humans, PPARg expression is increased in asthmatic airways, and is downregulated by steroid treatment. 66 Although PPARg expression correlates with indicators of airway remodeling, a cause-and-effect link has not been established. In fact, both the in vitro and animal studies described above suggest that activation of PPARg may have beneficial effects in asthma patients.…”