Elevated HMGB1 expression in COPD airways may sustain inflammation and remodeling through its interaction with IL-1beta and RAGE.

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.

YKL-40 is a chitin-binding protein that is elevated in patients with various inflammatory conditions associated with ongoing remodeling. We investigated whether the levels of YKL-40 were up-regulated in the circulation and the airways of patients with chronic obstructive pulmonary disease (COPD), and whether it promoted the production of inflammatory mediators from macrophages. Serum, bronchoalveolar lavage (BAL), bronchial biopsies, lung tissue specimens, and alveolar macrophages from never-smokers (n = 15), smokers without COPD (n = 20), and smokers with COPD (n = 30) were assessed for YKL-40 levels and immunolocalization. In addition, YKL-40-induced mediator release from alveolar macrophages was examined. We found that smokers with COPD had elevated levels of YKL-40 in serum (p ≤ 0.027) and BAL (p ≤ 0.007), more YKL-40-positive cells in bronchial biopsies (p ≤ 0.03), and a greater proportion of alveolar macrophages expressing YKL-40 than smokers without COPD or never-smokers. YKL-40 levels in serum and BAL were associated with airflow obstruction (pre-β2 agonist forced expiratory volume in 1 s, rs = −0.3892, p = 0.0072 and rs = −0.5491, p < 0.0001, respectively) and impaired diffusion lung capacity (transfer factor of the lung for carbon monoxide, rs = −0.4667, p = 0.002 and rs = −0.3854, p = 0.0045, respectively). TNF-α stimulated YKL-40 synthesis in alveolar macrophages from smokers with COPD, and exposure of these cells to YKL-40 promoted the release of IL-8, MCP-1, MIP-1α, and metalloproteinase-9. We conclude that YKL-40 is up-regulated in COPD, in which it may contribute to tissue inflammation and remodeling by sustaining the synthesis of proinflammatory and fibrogenic chemokines and of metalloproteinases by alveolar macrophages.