Metabolic Consequences of Adenosine Deaminase Deficiency in Mice Are Associated with Defects in Alveogenesis, Pulmonary Inflammation, and Airway Obstruction

doi:10.1084/jem.192.2.159

Published online 10 July 2000.

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© The Rockefeller University Press, 0022-1007/2000/7/159/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 2, July 17, 2000 159-170

Original Article

Metabolic Consequences of Adenosine Deaminase Deficiency in Mice Are Associated with Defects in Alveogenesis, Pulmonary Inflammation, and Airway Obstruction

Michael R. Blackburn^a, Jonathan B. Volmer^a, Janci L. Thrasher^a, Hongyan Zhong^a, Jeff R. Crosby^b, James J. Lee^b, and Rodney E. Kellems^a
^a Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston Medical School, Houston, Texas 77030
^b Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, Arizona 85259

Correspondence to: Michael R. Blackburn, University of Texas Health Science Center at Houston Medical School, Department of Biochemistry and Molecular Biology, 6431 Fannin St., Houston, TX 77030. Tel:713-500-6087 Fax:713-500-0652 E-mail:michael.r.blackburn{at}uth.tmc.edu.

Adenosine deaminase (ADA) is a purine catabolic enzyme thatmanages levels of the biologically active purines adenosineand 2'-deoxyadenosine in tissues and cells. ADA-deficient micedie at 3 wk of age from severe respiratory distress. This phenotypeis progressive and is linked to perturbations in pulmonary purinemetabolism. The inflammatory changes found in the lungs of ADA-deficientmice included an accumulation of activated alveolar macrophagesand eosinophils. These changes were accompanied by a pronouncedenlargement of alveolar spaces and increases in mucus productionin the bronchial airways. The alveolar enlargement was foundto be due in part to abnormal alveogenesis. Lowering adenosineand 2'-deoxyadenosine levels using ADA enzyme therapy decreasedthe pulmonary eosinophilia and resolved many of the lung histopathologies.In addition, genetically restoring ADA to the forestomach ofotherwise ADA-deficient mice prevented adenine metabolic disturbancesas well as lung inflammation and damage. These data suggestthat disturbances in purinergic signaling mediate the lung inflammationand damage seen in ADA-deficient mice.

Key Words: eosinophil, asthma, emphysema, alveolar macrophage, adenosinedeaminase

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