title: Dexamethasone blocks the systemic inflammation of alveolar hypoxia at several sites in the inflammatory cascade.
abstract: Alveolar hypoxia produces a rapid and widespread systemic inflammation in rats. The inflammation is initiated by the release into the circulation of monocyte chemoattractant protein-1 (MCP-1) from alveolar macrophages (AMO) activated by the low alveolar Po(2). Circulating MCP-1 induces mast cell (MC) degranulation with renin release and activation of the local renin-angiotensin system, leading to microvascular leukocyte recruitment and increased vascular permeability. We investigated the effect of dexamethasone, a synthetic anti-inflammatory glucocorticoid, on the development of the systemic inflammation of alveolar hypoxia and its site(s) of action in the inflammatory cascade. The inflammatory steps investigated were the activation of primary cultures of AMO by hypoxia, the degranulation of MCs by MCP-1 in the mesentery microcirculation of rats, and the effect of angiotensin II (ANG II) on the leukocyte/endothelial interface of the mesentery microcirculation. Dexamethasone prevented the mesentery inflammation in conscious rats breathing 10% O(2) for 4 h by acting in all key steps of the inflammatory cascade. Dexamethasone: 1) blocked the hypoxia-induced AMO activation and the release of MCP-1 and abolished the increase in plasma MCP-1 of conscious, hypoxic rats; 2) prevented the MCP-1-induced degranulation of mesentery perivascular MCs and reduced the number of peritoneal MCs, and 3) blocked the leukocyte-endothelial adherence and the extravasation of albumin induced by topical ANG II in the mesentery. The effect at each site was sufficient to prevent the AMO-initiated inflammation of hypoxia. These results may explain the effectiveness of dexamethasone in the treatment of the systemic effects of alveolar hypoxia.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KA 66160, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Chao
authors.forename: Zachary
authors.initials: Z
authors.lastname: Viets
authors.forename: Paula
authors.initials: P
authors.lastname: Donham
authors.forename: John G
authors.initials: JG
authors.lastname: Wood
authors.forename: Norberto C
authors.initials: NC
authors.lastname: Gonzalez
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D015550:Cell Degranulation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use*; D000860:Hypoxia / Q000503:physiopathology*; D007249:Inflammation / Q000188:drug therapy*; D016676:Macrophages, Alveolar / Q000187:drug effects; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D008643:Mesentery / Q000187:drug effects / Q000503:physiopathology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D000804:Angiotensin II; D003907:Dexamethasone