title: Lung inflammation and thymic atrophy after bleomycin are controlled by the prostaglandin D2 receptor DP1.
abstract: Acute lung injury (ALI) can be accompanied by secondary systemic manifestations. In a model of ALI induced by bleomycin (bleo), we examined the response of D prostanoid receptor 1 (DP1)-deficient mice (DP1(-/-)) to better understand these processes. DP1 deficiency aggravated the toxicity of bleo as indicated by enhanced body weight loss, mortality, and lung inflammation including bronchoalveolar permeability and neutrophilia. Thymic atrophy was also observed after bleo and was strongly exacerbated in DP1(-/-) mice. This resulted from the enhanced depletion of immature T lymphocytes in the thymus of DP1(-/-) mice, a phenomenon usually related to increased glucocorticoid release in blood. Serum corticosterone was more elevated in DP1(-/-) mice after bleo than in wild-type (wt) mice. Thymocytes of DP1(-/-) mice were not more sensitive to dexamethasone in vitro, and systemic delivery of dexamethasone or peritoneal inflammation after LPS induced a similar thymic atrophy in wt and DP1(-/-) mice, indicating that pulmonary DP1 was critical to the control of thymic atrophy after bleo. DP1(-/-) mice showed increased lung and/or blood mediators involved in neutrophil recruitment and/or glucocorticoid production/thymic atrophy (osteopontin, leukemia inhibitory factor, and keratinocyte-derived chemokine) after bleo. Finally, local pulmonary DP1 activation or inhibition in wt mice abrogated or amplified thymic atrophy after bleo, respectively. Altogether, our data reveal that ALI can perturb the systemic T-cell pool by inducing thymic atrophy and that both pathological processes are controlled by the pulmonary DP1 receptor. This new pathway represents a potential therapeutic target in ALI.
authors.affiliation: 1 Louvain Centre for Toxicology and Applied Pharmacology, and.
authors.forename: Sybille
authors.initials: S
authors.lastname: van den Brule
authors.forename: François
authors.initials: F
authors.lastname: Huaux
authors.forename: Francine
authors.initials: F
authors.lastname: Uwambayinema
authors.forename: Saloua
authors.initials: S
authors.lastname: Ibouraadaten
authors.forename: Yousof
authors.initials: Y
authors.lastname: Yakoub
authors.forename: Mihaly
authors.initials: M
authors.lastname: Palmai-Pallag
authors.forename: François
authors.initials: F
authors.lastname: Trottein
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.forename: Dominique
authors.initials: D
authors.lastname: Lison
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001284:Atrophy / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D001761:Bleomycin / Q000009:adverse effects; D001992:Bronchoalveolar Lavage Fluid; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D010539:Permeability; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D060168:Thymocytes / Q000378:metabolism / Q000502:physiology; D013950:Thymus Gland / Q000378:metabolism* / Q000473:pathology
chemical_list: D005938:Glucocorticoids; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D001761:Bleomycin; D003345:Corticosterone; C036293:prostaglandin D2 receptor