Allergic lung responses are increased in prostaglandin H synthase-deficient mice.
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 PGE(2) 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 PGE(2) in wild-type mice. We conclude that (a) PGHS-1 is the predominant enzyme that biosynthesizes PGE(2) 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.
Gavett
S H
SH
Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Madison
S L
SL
Chulada
P C
PC
Scarborough
P E
PE
Qu
W
W
Boyle
J E
JE
Tiano
H F
HF
Lee
C A
CA
Langenbach
R
R
Roggli
V L
VL
Zeldin
D C
DC
D000485:Allergens / Q000276:immunology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D006967:Hypersensitivity / Q000209:etiology*; D007073:Immunoglobulin E / Q000032:analysis; D007527:Isoenzymes / Q000172:deficiency / Q000502:physiology*; D007975:Leukotriene B4 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008170:Lung Compliance; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000502:physiology*
D000485:Allergens; D007527:Isoenzymes; D007975:Leukotriene B4; D007073:Immunoglobulin E; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone