Allergic lung responses are increased in prostaglandin H synthase–deficient 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
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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Allergic lung responses are increased in prostaglandin H synthase–deficient mice

Abstract

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.

Authors

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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Airway responsiveness to methacholine in PGHS-deficient and wild-type mi...
Airway responsiveness to methacholine in PGHS-deficient and wild-type mice. Wild-type, PGHS-1–/–, and PGHS-2–/– mice were divided into treatment groups as described in Figure 1. Airway responses to intravenous Mch were measured 1 day after final aerosol exposure, as described in Methods. Bars represent mean ± SE of 7–13 mice per group. (a) RT before dosing with Mch and at peak of response to 25, 50, 100, and 200 μg/kg Mch (left to right for each group). For each dose, significant differences among groups were determined for associated baselines (shown above hatched bars) and increases in RT due to Mch (shown above open bars). *P < 0.05 vs. all other groups. †P < 0.05 vs. wild-type saline. §P < 0.05 vs. all groups except wild-type OVA. (b) Total respiratory system-compliance (CT), measured simultaneously with RT, before dosing with Mch and at nadir of response to Mch. For each dose, significant differences among groups were determined for associated baselines (hatched bars + open bars; shown above open bars) and decreases in CT due to Mch (shown within open bars). *P < 0.05 vs. wild-type saline, wild-type OVA, PGHS-1–/– saline, and PGHS-2–/– saline. †P < 0.05 vs. PGHS-1–/– saline and PGHS-2–/– OVA. §P < 0.05 vs. wild-type OVA and PGHS-1–/– saline. ‡P < 0.05 vs. PGHS-2–/– saline.