To investigate the function of prostaglandin H synthase-1 and synthase-2 (PGHS-1 and PGHS-2) in the normal lung and in allergic lung responses, we examined allergen-induced pulmonary inflammation and airway hyperresponsiveness in wild-type mice and in PGHS-1–/– and PGHS-2–/– mice. Among nonimmunized saline-exposed groups, we found no significant differences in lung function or histopathology, although PGE2 was dramatically reduced in bronchoalveolar lavage (BAL) fluid from PGHS-1–/– mice, relative to wild-type or PGHS-2–/– mice. After ovalbumin sensitization and challenge, lung inflammatory indices (BAL cells, proteins, IgE, lung histopathology) were significantly greater in PGHS-1–/– mice compared with PGHS-2–/– mice, and both were far greater than in wild-type mice, as illustrated by the ratio of eosinophils in BAL fluid (8:5:1, respectively). Both allergic PGHS-1–/– and PGHS-2–/– mice exhibited decreased baseline respiratory system compliance, whereas only allergic PGHS-1–/– mice showed increased baseline resistance and responsiveness to methacholine. Ovalbumin exposure caused a modest increase in lung PGHS-2 protein and a corresponding increase in BAL fluid PGE2 in wild-type mice. We conclude that (a) PGHS-1 is the predominant enzyme that biosynthesizes PGE2 in the normal mouse lung; (b) PGHS-1 and PGHS-2 products limit allergic lung inflammation and IgE secretion and promote normal lung function; and (c) airway inflammation can be dissociated from the development of airway hyperresponsiveness in PGHS-2–/– mice.
Stephen H. Gavett, Sharon L. Madison, Patricia C. Chulada, Paula E. Scarborough, Wei Qu, James E. Boyle, Howard F. Tiano, Christopher A. Lee, Robert Langenbach, Victor L. Roggli, Darryl C. Zeldin
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