title: Airway inflammation and responsiveness in prostaglandin H synthase-deficient mice exposed to bacterial lipopolysaccharide.
abstract: 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 microg/m(3) 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-alpha, interleukin-6, and macrophage inflammatory protein-2), and PGE(2). 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 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 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.
authors.affiliation: National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Bldg. 101, Rm. D-236, Research Triangle Park, NC 27709, USA. zeldin@niehs.nih.gov
authors.forename: D C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: C
authors.initials: C
authors.lastname: Wohlford-Lenane
authors.forename: P
authors.initials: P
authors.lastname: Chulada
authors.forename: J A
authors.initials: JA
authors.lastname: Bradbury
authors.forename: P E
authors.initials: PE
authors.lastname: Scarborough
authors.forename: V
authors.initials: V
authors.lastname: Roggli
authors.forename: R
authors.initials: R
authors.lastname: Langenbach
authors.forename: D A
authors.initials: DA
authors.lastname: Schwartz
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D018925:Chemokines / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D007975:Leukotriene B4 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008168:Lung / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D011014:Pneumonia / Q000139:chemically induced / Q000503:physiopathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018925:Chemokines; D016207:Cytokines; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011506:Proteins; D007975:Leukotriene B4; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone