Asthma and lower airway diseaseChitotriosidase is the primary active chitinase in the human lung and is modulated by genotype and smoking habit
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Subjects and clinical samples
We studied biologic samples stored in the Airway Tissue Bank at the University of California, San Francisco, that had been collected during research bronchoscopy from 40 nonsmoking subjects with asthma, 25 habitual smokers without asthma, and 26 healthy nonsmoking control subjects (Table I).15 Asthmatic subjects had a prior physician's diagnosis of asthma, a PC20 methacholine value of less than 8 mg/mL, and were using only inhaled β-agonist medications for therapy (additional data on the asthma
Lung chitinase activity is modulated by pH and smoking habit
We measured total chitinase activity in the BAL fluid of 77 subjects, including 31 asthmatic subjects, 24 healthy subjects, and 22 habitual smokers, using a synthetic chitin substrate, 4-MU-(4-deoxy)chitobiose.21 This substrate is digested by both AMCase and CHIT1, but the pH profile for the activity of these 2 chitinolytic enzymes is distinct and can be used to infer whether CHIT1 or AMCase is the responsible enzyme for chitinase activity in a biologic sample. For example, previous studies
Discussion
We characterized the relative contribution of both active human chitinases, CHIT1 and AMCase, to chitinase activity in the lung from healthy subjects, asthmatic subjects, and habitual smokers. We determined CHIT1 to be the primary active chitinase in the lung, and we found that its expression is strongly dependent on genetics and on smoking habit.
We used a multifaceted approach to establish that CHIT1, but not AMCase, is the principal active chitinase in the human lung, including determination
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2022, European Journal of PharmacologyCitation Excerpt :In contrast, we were not able to obtain any evidence of AMCase expression in these studies. Our results are in accordance with several reports, which indicated that CHIT1 is the main source of the elevated chitinolytic activity (Bargagli et al., 2007; Chang et al., 2020; Seibold et al., 2008). In accordance with these results, the analysis of a single cell lung atlas (Reyfman et al., 2019) generated by scRNAseq of fibrotic and healthy lungs revealed a strong induction of CHIT1 in the lungs of patients with pulmonary fibrosis, which was restricted to a macrophage cluster specific to fibrotic lungs and not present in healthy lungs.
Comparative functional analysis between human and mouse chitotriosidase: Substitution at amino acid 218 modulates the chitinolytic and transglycosylation activity
2020, International Journal of Biological MacromoleculesCitation Excerpt :In addition, chitinase activity of AMCase in human is much lower than in mice due to arginine at position 61 instead of methionine that is present in mouse AMCase [29,30]. In human lungs, AMCase transcripts are present, however they are consistent with an isoform lacking enzymatic activity [31]. Thus, studying amino acid substitutions in enzymes such as AMCase is essential not only from biochemical but also from medical point of view [29,30,32].
Direct comparison of chitinolytic properties and determination of combinatory effects of mouse chitotriosidase and acidic mammalian chitinase
2019, International Journal of Biological Macromolecules
Supported by National Institutes of Health grants AI077439 (J.V.F. and E.G.B.), HL080414 (J.V.F.), HL078885 (E.G.B.), and RR17002 (P.G.W.); the Sandler Asthma Basic Research Center (J.V.F. and E.G.B.); and the Sandler Program for Asthma Research (E.G.B.).
Disclosure of potential conflict of interest: A. Innes has received research support from Genentech. P. G. Woodruff has received research support from Boehringer Ingelheim and Genentech. J. V. Fahy has received research support from Genentech, Roche, and Boehringer Ingelheim. The rest of the authors have declared that they have no conflict of interest.
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These authors contributed equally to this work.