Am. J. Respir. Cell Mol. Biol., Volume 25, Number 4, October, 2001 457-465

Airway Inflammation and Responsiveness in Prostaglandin H Synthase-Deficient Mice Exposed to Bacterial Lipopolysaccharide

Darryl C. Zeldin, Chris Wohlford-Lenane, Patricia Chulada, J. Alyce Bradbury, Paula E. Scarborough, Victor Roggli, Robert Langenbach, and David A. Schwartz

National Institute of Environmental Health Sciences, Research Triangle Park; and Duke University Medical Center, Durham, North Carolina

Bacterial lipopolysaccharide (LPS) is a risk factor for exacerbation of asthma and causes airway inflammation. The aim of this study was to examine the effects of disruption of prostaglandin (PG) H synthase (PGHS)-1 and PGHS-2 genes on pulmonary responses to inhaled LPS. PGHS-1^/, PGHS-2^/, and wild-type (WT) mice were exposed to 4 to 6 µg/m³ LPS via aerosol. Enhanced pause (PenH), a measure of bronchoconstriction, was assessed using a whole-body plethysmograph before and immediately after a 4-h LPS exposure. Bronchoalveolar lavage (BAL) was performed after LPS exposure to assess inflammatory cells, cytokines/chemokines (tumor necrosis factor-, interleukin-6, and macrophage inflammatory protein-2), and PGE₂. The degree of lung inflammation was scored on hematoxylin-and-eosin-stained sections. PGHS-1 and PGHS-2 protein levels were determined by immunoblotting. All mice exhibited increased PenH and methacholine responsiveness after LPS exposure; however, these changes were much more pronounced in PGHS-1^/ and PGHS-2^/ mice relative to WT mice (P < 0.05). There were no significant differences in inflammation as assessed by BAL fluid (BALF) cells or lung histology between the genotypes despite reduced BALF cytokines/chemokines and PGE₂ in PGHS-1^/ and PGHS-2^/ mice relative to WT mice (P < 0.05). PGHS-2 was upregulated more in PGHS-1^/ mice compared with WT mice after LPS exposure. We conclude that: (1) airway inflammation and hyperresponsiveness are dissociated in PGHS-1^/ and PGHS-2^/ mice exposed to LPS; (2) the balance of PGHS-1 and PGHS-2 is important in regulating the functional respiratory responses to inhaled LPS; and (3) neither PGHS-1 nor PGHS-2 is important in regulating basal lung function or the inflammatory responses of the lung to inhaled LPS.

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