Lung Inflammation and Thymic Atrophy After Bleomycin are Controlled by the PGD2 Receptor DP1.

American journal of respiratory cell and molecular biology

PubMedID: 24003988

van den Brule S, Huaux F, Uwambayinema F, Ibouraadaten S, Yakoub Y, Palmai-Pallag M, Trottein F, Renauld JC, Lison D. Lung Inflammation and Thymic Atrophy After Bleomycin are Controlled by the PGD2 Receptor DP1. Am J Respir Cell Mol Biol. 2013;.
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 deficient mice, a phenomenon usually related to increased glucocorticoid release in blood. Serum corticosterone was more elevated in DP1-/- mice after bleo than in wt. Thymocytes of DP1-/- mice were not more sensitive to dexamethasone (dex) in vitro and systemic delivery of dex or peritoneal inflammation after LPS induced a similar thymic atrophy in wt and DP1-/-, indicating that pulmonary DP1 was critical to control thymic atrophy after bleo. DP1 deficient 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.