The exaggerated expression of chitinase-like protein YKL-40, the human homolog of BRP-39, has been reported in a number of diseases including chronic obstructive pulmonary disease (COPD). However, in vivo role(s) of YKL-40 in normal physiology or in the pathogenesis of specific diseases such as COPD are still 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 wild type and BRP-39 null mutant mice (BRP-39-/-) were exposed to room air (RA) and CS for up to 10 months. The BRP-39 expression was significantly induced in macrophages, airway epithelial cells, and alveolar type II cells in the lungs of CS-exposed mice compared to RA-exposed mice, at least in part, via an IL-18 signaling dependent pathway. Null mutation of BRP-39 significantly reduced CS-induced BAL and tissue inflammation. However, CS-induced epithelial cell apoptosis and alveolar destruction were further enhanced in the absence of BRP-39. Consistent with the findings in mice, the tissue expression of YKL-40 was significantly increased in the lungs of current smokers compared to the lungs of ex-smokers or nonsmokers. In addition, the serum levels of YKL-40 were significantly higher in smokers with COPD than 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 highlight that maintaining the physiologic levels of YKL-40 in the lung will be therapeutically important to prevent excessive inflammatory responses or emphysematous alveolar destruction.
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