A Chitinase-like Protein in the Lung and Circulation of Patients with Severe Asthma
Geoffrey L. Chupp, M.D., Chun Geun Lee, M.D., Ph.D., Nizar Jarjour, M.D., Yun Michael Shim, M.D., Carole T. Holm, R.N., Susan He, M.D., James D. Dziura, Ph.D., M.P.H., Jennifer Reed, Ph.D., Anthony J. Coyle, Ph.D., Peter Kiener, Ph.D., Mark Cullen, M.D., Martine Grandsaigne, Marie-Christine Dombret, M.D., Michel Aubier, M.D., Marina Pretolani, Ph.D., and Jack A. Elias, M.D.
Background The evolutionarily conserved 18-glycosyl-hydrolasefamily contains true chitinases and chitinase-like proteinsthat lack enzymatic activity. Acidic mammalian chitinase hasrecently been associated with animal models of asthma. The relatedchitinase-like protein, YKL-40 (also called human cartilageglycoprotein 39 [HCgp-39] and chitinase 3–like 1), canbe readily measured in the serum. However, its relationshipto asthma has not been evaluated.
Methods We quantified serum YKL-40 levels in three cohorts ofpatients with asthma — one recruited from the patientpopulation at Yale University, one from the University of Paris,and one from the University of Wisconsin — as well asin controls from the surrounding communities. In the Paris cohort,immunohistochemical analysis and morphometric quantitation wereused to evaluate the locus of expression of YKL-40 in the lung.The clinical characteristics of the patients with high serumor lung YKL-40 levels were also evaluated.
Results Serum YKL-40 levels were significantly elevated in patientswith asthma as compared with controls. In the Paris cohort,lung YKL-40 levels were elevated and were correlated with circulatingYKL-40 levels (r=0.55, P<0.001) and with airway remodeling(measured as the thickness of the subepithelial basement membrane)(r=0.51, P=0.003). In all three cohorts, serum YKL-40 levelscorrelated positively with the severity of asthma and inverselywith the forced expiratory volume in 1 second. Patients withelevated levels of YKL-40 had significantly more frequent rescue-inhaleruse, greater oral corticosteroid use, and a greater rate ofhospitalization than patients with lower levels.
Conclusions YKL-40 is found in increased quantities in the serumand lungs in a subgroup of patients with asthma, in whom expressionof chitinase in both compartments correlates with the severityof asthma. The recovery of YKL-40 from these patients indicateseither a causative or a sentinel role for this molecule in asthma.
Source Information
From the Yale University School of Medicine, New Haven, CT (G.L.C., C.G.L., Y.M.S., C.T.H., S.H., J.D.D., M.C., J.A.E.); the University of Wisconsin School of Medicine, Madison (N.J.); MedImmune, Gaithersburg, MD (J.R., A.J.C., P.K.); and INSERM Unité 700, Université Paris 7 (M.G., M.A., M.P.), and Centre Hospitalier Universitaire Bichat Claude Bernard (M.-C.D., M.A.) — both in Paris. Drs. Pretolani and Elias contributed equally to this article.
Address reprint requests to Dr. Chupp or Dr. Elias at the Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, P.O. Box 208057, 300 Cedar St., TAC 441, New Haven, CT 06520, or at geoffrey.chupp{at}yale.edu or jack.elias{at}yale.edu.
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