Prostaglandin E(2) exerts homeostatic regulation of pulmonary vascular remodeling in allergic airway inflammation.
Nonselective inhibition of PG synthesis augments inflammation in mouse models of airway disease, but the roles of individual PGs are not completely clarified. To investigate the role of PGE(2) in a mouse model of airway inflammation induced by a natural allergen, we used mice lacking the critical terminal synthetic enzyme, microsomal PGE(2) synthase (mPGES)-1. Mice lacking mPGES-1 (ptges(-/-) mice) and wild-type C57BL/6 controls were challenged intranasally with low doses of an extract derived from the house dust mite Dermatophagoides farinae (Der f). The levels of PGE(2) in the bronchoalveolar lavage fluids of Der f-treated ptges(-/-) mice were approximately 80% lower than the levels in wild-type controls. Der f-induced bronchovascular eosinophilia was modestly enhanced in the ptges(-/-) mice. Both Der f-treated strains showed similar increases in serum IgE and IgG1, as well as comparable levels of Th1, Th2, and Th17 cytokine production by Der f-stimulated spleen cells. These findings indicated that mPGES-1-derived PGE(2) was not required for allergen sensitization or development of effector T cell responses. Unexpectedly, the numbers of vascular smooth muscle cells and the thickness of intrapulmonary vessels were both markedly increased in the Der f-treated ptges(-/-) mice. These vascular changes were suppressed by the administration of the stable PGE(2) analog 16, 16-dimethyl PGE(2), or of selective agonists of the E-prostanoid (EP) 1, EP2, and EP3 receptors, respectively, for PGE(2). Thus, mPGES-1 and its product, PGE(2), protect the pulmonary vasculature from remodeling during allergen-induced pulmonary inflammation, and these effects may be mediated by more than one EP receptor.
Lundequist
Anders
A
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Nallamshetty
Samridhi N
SN
Xing
Wei
W
Feng
Chunli
C
Laidlaw
Tanya M
TM
Uematsu
Satoshi
S
Akira
Shizuo
S
Boyce
Joshua A
JA
D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D015232:Dinoprostone / Q000276:immunology*; D006706:Homeostasis / Q000276:immunology*; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics; D008168:Lung / Q000098:blood supply* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D011014:Pneumonia / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D000071876:Prostaglandin-E Synthases
D039741:Antigens, Dermatophagoides; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone