Chitinase 1 Is a Biomarker for and Therapeutic Target in Scleroderma-Associated Interstitial Lung Disease That Augments TGF-β1 Signaling

Abstract

Interstitial lung disease (ILD) with pulmonary fibrosis is an important manifestation in systemic sclerosis (SSc, scleroderma) where it portends a poor prognosis. However, biomarkers that predict the development and or severity of SSc-ILD have not been validated, and the pathogenetic mechanisms that engender this pulmonary response are poorly understood. In this study, we demonstrate in two different patient cohorts that the levels of chitotriosidase (Chit1) bioactivity and protein are significantly increased in the circulation and lungs of SSc patients compared with demographically matched controls. We also demonstrate that, compared with patients without lung involvement, patients with ILD show high levels of circulating Chit1 activity that correlate with disease severity. Murine modeling shows that in comparison with wild-type mice, bleomycin-induced pulmonary fibrosis was significantly reduced in Chit1−/− mice and significantly enhanced in lungs from Chit1 overexpressing transgenic animals. In vitro studies also demonstrated that Chit1 interacts with TGF-β1 to augment fibroblast TGF-β receptors 1 and 2 expression and TGF-β–induced Smad and MAPK/ERK activation. These studies indicate that Chit1 is potential biomarker for ILD in SSc and a therapeutic target in SSc-associated lung fibrosis and demonstrate that Chit1 augments TGF-β1 effects by increasing receptor expression and canonical and noncanonical TGF-β1 signaling.

Curcumin protects the developing lung against long-term hyperoxic injury

“…This dose is markedly lower than those used in adults by others, either by the oral or parenteral route (6,10,12,25). Our previous investigation into the mechanism of curcumin's cytoprotective effect on neonatal lung injury suggested blockade of hyperoxia-induced TGF-␤ activation, which modulates fibroblast differentiation via both canonical (Smad) and noncanonical (MAP kinase) pathways (13,23,33,35). In line with previous observations in a variety of models, we now for the first time document blockade of hyperoxia-induced activation of TGF-␤ and its downstream noncanonical mediator Erk1/2 by curcumin (4,23,26).…”

Interstitial lung disease in systemic sclerosis: where do we stand?

“…A meta-analysis of 26 studies identified male sex, disease extent on HRCT, presence of honeycombing, elevated Krebs von den Lungen (KL-6) values and increased alveolar epithelial permeability as predictors of both mortality and ILD progression in unadjusted analysis, while disease extent on the HRCT scan was the only variable that independently predicted both mortality and ILD progression [39]. Recently, a loss of density on capillaroscopy was shown to be associated with worse FVC and DLCO [40] and biomarkers that correlate with the severity of fibrosis have been proposed: elevated levels of chitinase [41], tenascin C [42], growth differentiation protein 15 [43], cartilage oligomeric matrix protein, alveolar epithelial cell antigen, KL-6 [44] and the chemokine CXCL4 [45]. Serum IL-6 predicted early disease progression and IL-6 values >767 pg·mL −1 were predictive of risk of death within the first 30 months in patients with mild SSc-ILD [46].…”

Chitotriosidase: A New Inflammatory Marker in Diabetic Complications

“…Studies with genetically modified mice demonstrated that CHIT1 enhances TGF-β1 receptor expression and signaling, suggesting a role in initiating or amplifying the response to organ injury [58]. In addition, it was demonstrated that heterozygosis for a 24-bp duplication in the CHIT1 gene protects from nonalcoholic fatty liver disease progression [59].…”