Am. J. Respir. Crit. Care Med., Volume 164, Number 8, October 2001, 1487-1494

Regulation of Peroxisome Proliferator-activated Receptor  Expression in Human Asthmatic Airways
Relationship with Proliferation, Apoptosis, and Airway Remodeling

LAURENT BENAYOUN, SÉVERINE LETUVE, ANNE DRUILHE, JORGE BOCZKOWSKI, MARIE-CHRISTINE DOMBRET, PATRICIA MECHIGHEL, JÉRÔME MEGRET, GUY LESECHE, MICHEL AUBIER, and MARINA PRETOLANI

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 408, Faculté de Médecine Xavier Bichat, Paris; Service de Chirurgie Thoracique, Hôpital Beaujon, Clichy, France

Airway inflammation and alterations in cellular turnover are histopathologic features of asthma. We show that the expression of peroxisome proliferator-activated receptor  (PPAR), 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 expression in the epithelium correlates positively with SBM thickening and collagen deposition, whereas PPAR expressing cells in the submucosa relate both to SBM thickening and to the number of proliferating cells. The intensity of PPAR expression in the bronchial submucosa, the airway epithelium, and the smooth muscle is negatively related to FEV₁ values. Inhaled steroids alone, or associated with oral steroids, downregulate PPAR 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 (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.

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