title: Inhaled sulfur dioxide causes pulmonary and systemic inflammation leading to fibrotic respiratory disease in a rat model of chemical-induced lung injury.
abstract: Inhalation of high concentrations of sulfur dioxide (SO2) affects the lungs and can be immediately dangerous to life. We examined the development of acute and long-term effects after exposure of SO2in Sprague-Dawley rats, in particular inflammatory responses, airway hyperresponsiveness (AHR) and lung fibrosis. Animals were subjected to a single exposure of 2200ppm SO2during 10min and treated with a single dose of the anti-inflammatory corticosteroid dexamethasone 1h following exposure. Exposed rats showed labored breathing, decreased body-weight and an acute inflammation with neutrophil and macrophage airway infiltrates 5h post exposure. The acute effects were characterized by bronchial damage restricted to the larger bronchi with widespread injured mucosal epithelial lining. Rats displayed hyperreactive airways 24h after exposure as indicated by increased methacholine-induced respiratory resistance. The inflammatory infiltrates remained in lung tissue for at least 14 days but at the late time-point the dominating granulocyte types had changed from neutrophils to eosinophils. Analysis of immunoregulatory and pro-inflammatory cytokines in serum and airways implicated mixed macrophage phenotypes (M1/M2) and T helper cell activation of both TH1 and TH2 subtypes. Increased expression of the pro-fibrotic cytokine TGFβ1 was detected in airways 24h post exposure and remained increased at the late time-points (14 and 28 days). The histopathology analysis confirmed a significant collagen deposition 14 days post exposure. Treatment with dexamethasone significantly counteracted the acute inflammatory response but was insufficient for complete protection against SO2-induced adverse effects, i.e. treatment only provided partial protection against AHR and the long-term fibrosis.
authors: Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
authors: Elisabeth
authors: E
authors: Wigenstam
authors: Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
authors: Linda
authors: L
authors: Elfsmark
authors: Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden; Department of Public Health and Clinical Medicine, Unit of Respiratory Medicine, Umeå University, Umeå, Sweden, Sweden.
authors: Anders
authors: A
authors: Bucht
authors: Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden. Electronic address: sofia.jonasson@foi.se.
authors: Sofia
authors: S
authors: Jonasson
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D016210:Methacholine Chloride / Q000633:toxicity; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000188:drug therapy; D013458:Sulfur Dioxide / Q000008:administration & dosage / Q000633:toxicity*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D053773:Transforming Growth Factor beta1; D013458:Sulfur Dioxide; D016210:Methacholine Chloride; D003907:Dexamethasone
keywords: Chemical-induced lung injury; Corticosteroids; Inflammation; Respiratory mechanics; Sulfur dioxide