Chitinase 3–Like 1 Suppresses Injury and Promotes Fibroproliferative Responses in Mammalian Lung Fibrosis

Abstract

Epithelial injury, alternative macrophage accumulation, and fibroproliferation coexist in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Chitinase 3–like 1 (CHI3L1) is a prototypic chitinase-like protein that has been retained over species and evolutionary time. However, the regulation of CHI3L1 in IPF and its ability to regulate injury and/or fibroproliferative repair have not been fully defined. We demonstrated that CHI3L1 levels were elevated in patients with IPF. High levels of CHI3L1 are associated with progression—as defined by lung transplantation or death—and with scavenger receptor–expressing circulating monocytes in an ambulatory IPF population. In preterminal acute exacerbations of IPF, CHI3L1 levels were reduced and associated with increased levels of apoptosis. We also demonstrated that in bleomycin-treated mice, CHI3L1 expression was acutely and transiently decreased during the injury phase and returned toward and eventually exceeded baseline levels during the fibrotic phase. In this model, CHI3L1 played a protective role in injury by ameliorating inflammation and cell death, and a profibrotic role in the repair phase by augmenting alternative macrophage activation, fibroblast proliferation, and matrix deposition. Using three-dimensional culture system of a human fibroblast cell line, we found that CHI3L1 is sufficient to induce low grade myofibroblast transformation. In combination, these studies demonstrate that CHI3L1 is stimulated in IPF, where it represents an attempt to diminish injury and induce repair. They also demonstrate that high levels of CHI3L1 are associated with disease progression in ambulatory patients and that a failure of the CHI3L1 antiapoptotic response might contribute to preterminal disease exacerbations.

Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

“…First, studies from our laboratory have demonstrated that oxidant injury is a powerful inhibitor of CHI3L1 and that if oxidant inhibition of CHI3L1 is prevented, oxidant injury and lung epithelial cell apoptosis are abrogated (36). Similar results were found in experiments with bleomycin (27). This suggests that a decrease in CHI3L1 appears to be a prerequisite for agents such as hyperoxia or bleomycin to induce the acute and severe tissue injury and alveolar epithelial cell death responses that they generate.…”

“…Importantly, the majority the first time to our knowledge, that this binding plays a critical role in CHI3L1-induced fibroproliferative repair. In accordance with the importance of M2 macrophages and fibroblast activation in fibrogenesis (27), these studies also demonstrate that CRTH2 plays a key role in CHI3L1-induced M2 macrophage differentiation and allow for the speculation that CRTH2 also plays a role in fibroblast proliferation and activation and other fibroproliferative events.…”

“…Bleomycin is well known to induce acute injury and later fibroproliferative responses in the lung. One of the interesting findings in these and previous (27) studies was that the levels of CHI3L1 decreased during the former and increased remarkably during the latter. On superficial analysis it is hard to understand how these divergent responses both contribute to the generation of pulmonary fibrosis.…”

“…In addition, the exaggerated fibrosis that was caused by activation of the CHI3L1 transgene activation during fibroproliferative repair was also abrogated by CRTH2 inhibition ( Figure 7D). Because M2 macrophages play an important role in fibrogenesis and studies from our laboratory have demonstrated that CHI3L1 is a powerful stimulator of M2 macrophage differentiation (27), studies were undertaken to determine whether CRTH2 played an important role in this response. As shown in Figure 7, E-G, CRTH2 plays an essential role in CHI3L1-induced M2 macrophage differentiation in vivo and in vitro.…”

“…15,26). In many of these disorders, CHI3L1 is likely produced as a protective response based on its ability to simultaneously decrease epithelial cell apoptosis while stimulating fibroproliferative repair (27). Recent studies from our laboratory have defined IL-13Rα2 as the first receptor for any GH 18 moiety and have demonstrated that it mediates many of the effects of CHI3L1 (28).…”