The Journal of Allergy and Clinical Immunology
Volume 122, Issue 5 , Pages 944-950.e3, November 2008

Chitotriosidase is the primary active chitinase in the human lung and is modulated by genotype and smoking habit

  • Max A. Seibold, PhD

      Affiliations

    • Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, Calif
    • Biopharmaceutical Sciences, University of California, San Francisco, Calif
    • These authors contributed equally to this work.
    • ,
  • Samantha Donnelly, PhD

      Affiliations

    • Cardiovascular Research Institute, University of California, San Francisco, Calif
    • These authors contributed equally to this work.
    • ,
  • Margaret Solon, BA

      Affiliations

    • Cardiovascular Research Institute, University of California, San Francisco, Calif
    • ,
  • Anh Innes, MD

      Affiliations

    • Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, Calif
    • Cardiovascular Research Institute, University of California, San Francisco, Calif
    • ,
  • Prescott G. Woodruff, MD, MPH

      Affiliations

    • Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, Calif
    • Cardiovascular Research Institute, University of California, San Francisco, Calif
    • ,
  • Rolf G. Boot, PhD

      Affiliations

    • Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    • ,
  • Esteban González Burchard, MD, MPH

      Affiliations

    • Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, Calif
    • Biopharmaceutical Sciences, University of California, San Francisco, Calif
    • Lung Biology Center, University of California, San Francisco, Calif
    • Institute for Human Genetics of the University of California, San Francisco, Calif
    • ,
  • John V. Fahy, MD, MSc

      Affiliations

    • Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, Calif
    • Cardiovascular Research Institute, University of California, San Francisco, Calif
    • Corresponding Author InformationReprint requests: John V. Fahy, MD, MSc, Box 0111, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA 94143.

Received 12 May 2008; received in revised form 19 August 2008; accepted 21 August 2008. published online 10 October 2008.

Background

Chitinolytic enzymes play important roles in the pathophysiology of allergic airway responses in mouse models of asthma. Acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1) have chitinolytic activity, but relatively little is known about their expression in human asthma.

Objective

We sought to determine the expression and activity of AMCase and CHIT1 in healthy subjects, subjects with asthma, and habitual smokers, taking account of the null 24-bp duplication in the CHIT1 gene.

Methods

We measured chitinase activity in bronchoalveolar lavage (BAL) fluid at multiple pHs by using a synthetic chitin substrate. We also determined AMCase and CHIT1 gene expression in epithelial brushings and BAL fluid macrophages by means of real time RT-PCR. Paired DNA samples were genotyped for the CHIT1 duplication.

Results

In all subgroups the pH profile of chitinase activity in BAL fluid matched that of CHIT1, but not AMCase, and chitinase activity was absent in subjects genetically deficient in active CHIT1. Although AMCase protein was detectable in lavage fluid, AMCase transcripts in macrophages were consistent with an isoform lacking enzymatic activity. Median chitinase activity in BAL fluid tended to be lower than normal in asthmatic subjects but was increased 7-fold in habitual smokers, where CHIT1 gene expression in macrophages was increased.

Conclusions

Chitinase activity in the lung is the result of CHIT1 activity. Although AMCase protein is detectable in the lung, our data indicate that it is inactive. Chitinase activity is not increased in subjects with asthma and in fact tends to be decreased. The high levels of chitinase activity in habitual smokers result from upregulation of CHIT1 gene expression, especially in macrophages.

Key words: AMCase, CHIT1, chitinase, asthma, smokers, bronchoalveolar lavage

Abbreviations used: AMCase, Acidic mammalian chitinase, BAL, Bronchoalveolar lavage, CHIT1, Chitotriosidase, CHI3LI, Chitinase-3-like-1, COPD, Chronic obstructive pulmonary disease

 

 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.

PII: S0091-6749(08)01542-X

doi:10.1016/j.jaci.2008.08.023

The Journal of Allergy and Clinical Immunology
Volume 122, Issue 5 , Pages 944-950.e3, November 2008

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