title: Suppression of inflammatory cell trafficking and alveolar simplification by the heme oxygenase-1 product carbon monoxide.
abstract: Bronchopulmonary dysplasia (BPD), a lung disease of prematurely born infants, is characterized in part by arrested development of pulmonary alveolae. We hypothesized that heme oxygenase (HO-1) and its byproduct carbon monoxide (CO), which are thought to be cytoprotective against redox stress, mitigate lung injury and alveolar simplification in hyperoxia-exposed neonatal mice, a model of BPD. Three-day-old C57BL/6J mice were exposed to air or hyperoxia (FiO2, 75%) in the presence or absence of inhaled CO (250 ppm for 1 h twice daily) for 21 days. Hyperoxic exposure increased mean linear intercept, a measure of alveolar simplification, whereas CO treatment attenuated hypoalveolarization, yielding a normal-appearing lung. Conversely, HO-1-null mice showed exaggerated hyperoxia-induced hypoalveolarization. CO also inhibited hyperoxia-induced pulmonary accumulation of F4/80+, CD11c+, and CD11b+ monocytes and Gr-1+ neutrophils. Furthermore, CO attenuated lung mRNA and protein expression of proinflammatory cytokines, including the monocyte chemoattractant CCL2 in vivo, and decreased hyperoxia-induced type I alveolar epithelial cell CCL2 production in vitro. Hyperoxia-exposed CCL2-null mice, like CO-treated mice, showed attenuated alveolar simplification and lung infiltration of CD11b+ monocytes, consistent with the notion that CO blocks lung epithelial cell cytokine production. We conclude that, in hyperoxia-exposed neonatal mice, inhalation of CO suppresses inflammation and alveolar simplification.
authors: Univ. of Michigan, 7220 C, Medical Science Research Bldg. III, 1150 West Medical Center Dr., Ann Arbor, MI 48109-0644 (e-mail address: dpinsky@umich.edu.
authors: Anuli C
authors: AC
authors: Anyanwu
authors: J Kelley
authors: JK
authors: Bentley
authors: Antonia P
authors: AP
authors: Popova
authors: Omar
authors: O
authors: Malas
authors: Husam
authors: H
authors: Alghanem
authors: Adam M
authors: AM
authors: Goldsmith
authors: Marc B
authors: MB
authors: Hershenson
authors: David J
authors: DJ
authors: Pinsky
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000963:Antimetabolites / Q000494:pharmacology*; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000502:physiology*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D018496:Hyperoxia / Q000188:drug therapy / Q000503:physiopathology*; D007124:Immunoenzyme Techniques; D016676:Macrophages, Alveolar; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes; D010100:Oxygen / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000963:Antimetabolites; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D010100:Oxygen
keywords: CCL2; CD11b; bronchopulmonary dysplasia; macrophage; neonatal lung injury