Role of Breast Regression Protein–39 in the Pathogenesis of Cigarette Smoke–Induced Inflammation and Emphysema

Abstract

The exaggerated expression of chitinase-like protein YKL-40, the human homologue of breast regression protein-39 (BRP-39), was reported in a number of diseases, including chronic obstructive pulmonary disease (COPD). However, the in vivo roles of YKL-40 in normal physiology or in the pathogenesis of specific diseases such as COPD remain poorly understood. We hypothesized that BRP-39/YKL-40 plays an important role in the pathogenesis of cigarette smoke (CS)-induced emphysema. To test this hypothesis, 10-week-old wildtype and BRP-39 null mutant mice (BRP-39 2/2 ) were exposed to room air (RA) and CS for up to 10 months. The expression of BRP-39 was significantly induced in macrophages, airway epithelial cells, and alveolar Type II cells in the lungs of CS-exposed mice compared with RA-exposed mice, at least in part via an IL-18 signaling-dependent pathway. The null mutation of BRP-39 significantly reduced CSinduced bronchoalveolar lavage and tissue inflammation. However, CS-induced epithelial cell apoptosis and alveolar destruction were further enhanced in the absence of BRP-39. Consistent with these findings in mice, the tissue expression of YKL-40 was significantly increased in the lungs of current smokers compared with the lungs of ex-smokers or nonsmokers. In addition, serum concentrations of YKL-40 were significantly higher in smokers with COPD than in nonsmokers or smokers without COPD. These studies demonstrate a novel regulatory role of BRP-39/YKL-40 in CS-induced inflammation and emphysematous destruction. These studies also underscore that maintaining physiologic concentrations of YKL-40 in the lung is therapeutically important in preventing excessive inflammatory responses or emphysematous alveolar destruction.

YKL-40/CHI3L1 drives inflammation on the road of tumor progression

“…There was a significant reduction in CS-induced bronchoalveolar lavage and tissue inflammation in YKL-40/ CHI3L1 KO mice [50]. Significantly, epithelial cell apoptosis and alveolar destruction were enhanced further in the YKL-40/ CHI3L1 KO mice [50]. These findings suggest that YKL-40/ CHI3L1 is involved in preventing apoptosis in lung-related diseases.…”

“…ELISA of plasma samples from patients with moderate-to-severe COPD showed high YKL-40/ CHI3L1 expression in severe COPD patients, and this was correlated with increased mortality [49]. In another study, it was demonstrated that YKL-40/CHI3L1 levels were higher in smokers with COPD than those without COPD [50]. Upregulation of YKL-40/CHI3L1 expression in the lungs of COPD patients is known to contribute to tissue inflammation, airway remodeling, and activation of alveolar macrophages [17].…”

“…In addition to macrophages, YKL-40/CHI3L1 is upregulated in airway epithelial cells and alveolar type II cells in the lungs of CS-exposed mice compared with room air-exposed mice [50]. There was a significant reduction in CS-induced bronchoalveolar lavage and tissue inflammation in YKL-40/ CHI3L1 KO mice [50]. Significantly, epithelial cell apoptosis and alveolar destruction were enhanced further in the YKL-40/ CHI3L1 KO mice [50].…”

“…YKL-40/CHI3L1 induced the expression of proinflammatory mediators, such as IL-8/CXCL2, MCP-1/CCL2, and MMP-9, as assessed by ELISA, in alveolar macrophages from smokers with COPD [17]. In addition to macrophages, YKL-40/CHI3L1 is upregulated in airway epithelial cells and alveolar type II cells in the lungs of CS-exposed mice compared with room air-exposed mice [50]. There was a significant reduction in CS-induced bronchoalveolar lavage and tissue inflammation in YKL-40/ CHI3L1 KO mice [50].…”

Lung Diseases - Selected State of the Art Reviews

“…In regard to the nerves, many studies have shown synergistic interactions between spasmogens and electrical stimulation of the vagal nerves (17,33,57,88,114,137,217,258). Similarly, a decrease in responsiveness to spasmogens (other than ACh (88)) was observed following vagotomy (59,137,157,258), cooling of the vagal nerves (58,88), or treatments with either atropine (59,219), tetrodotoxin (219) or hexamethonium (59). These results suggest that the basal cholinergic tone synergistically interacts with the exogenously delivered spasmogen.…”