Airway inflammation and responsiveness in prostaglandin H synthase-deficient mice exposed to bacterial lipopolysaccharide

Bacterial lipopolysaccharide (LPS) is a risk factor for exacerbation of ast hma and causes airway inflammation, The aim of this study was to examine th e effects of disruption of prostaglandin (PG) H synthase (PGHS)-1 and PGHS- 2 genes on pulmonary responses to inhaled LPS. PGHS-1(-/-), PGHS-2(-/-), an wild-type (WT) mice were exposed to 4 to 6 mug/m(3) LPS via aerosol. Enhan ced pause (PenH), a measure of bronchoconstriction, was assessed using a wh ole-body plethysmograph before and immediately after a 4-h LPS exposure. Br onchoalveolar lavage (BAL) was performed after LPS exposure to assess infla mmatory cells, cytokines/chemokines (tumor necrosis factor-alpha, interleuk in-6, and macrophage inflammatory protein-2), and PGE(2). The degree of lun g inflammation was scored on hematoxylin-and-eosin-stained sections. PGHS-1 and PGHS-2 protein levels were determined by immunoblotting. All mice exhi bited increased PenH and methacholine responsiveness after LPS exposure; ho wever, these changes were much more pronounced in PGHS-1(-/-) and PGHS-2(-/ -) mice relative to WT mice (P < 0.05). There were no significant differenc es in inflammation as assessed by BAL fluid (BALF) cells or lung histology between the genotypes despite reduced BALF cytokines/chemokines and PGE(2). 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 e xposure. 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 res piratory responses to inhaled LPS; and (3) neither PGHS-1 nor PGHS-2 is imp ortant in regulating basal lung function or the inflammatory responses of t he lung to inhaled LPS.