title: Antenatal Ureaplasma urealyticum respiratory tract infection stimulates proinflammatory, profibrotic responses in the preterm baboon lung.
abstract: Chronic inflammation and fibrosis are hallmarks of lung pathology of newborn Ureaplasma infection. We hypothesized that antenatally acquired Ureaplasma stimulates a chronic inflammatory, profibrotic immune response that contributes to lung injury, altered developmental signaling, and fibrosis. Lung specimens from 125-d gestation baboon newborns ventilated for 14 d that were either infected antenatally with Ureaplasma serovar 1 or noninfected, and 125-d and 140-d gestational controls were obtained from the Baboon BPD Resource Center (San Antonio, TX). Trichrome stain to assess fibrosis and immunohistochemistry for alpha-smooth muscle actin (alpha-SMA) and transforming growth factor beta1 (TGFbeta1) were performed. Lung homogenates were analyzed by enzyme-linked immunosorbent assay (ELISA) for cytokines [tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1beta, TGFbeta1, oncostatin M (OSM), IL-10, and interferon gamma (IFNgamma)] and the chemokine MCP-1 and by Western blot for Smad2, Smad3, and Smad7. Compared with noninfected ventilated and gestational controls, Ureaplasma-infected lungs demonstrated more extensive fibrosis, increased alpha-SMA and TGFbeta1 immunostaining, and higher concentrations of active TGFbeta1, IL-1beta, and OSM, but no difference in IL-10 levels. There was a trend toward higher Smad2/Smad7 and Smad3/Smad7 ratios in Ureaplasma lung homogenates, consistent with up-regulation of TGFbeta1 signaling. Collectively, these data suggest that a prolonged proinflammatory response initiated by intrauterine Ureaplasma infection contributes to early fibrosis and altered developmental signaling in the immature lung.
authors.affiliation: Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA. rviscard@umaryland.edu
authors.forename: Rose M
authors.initials: RM
authors.lastname: Viscardi
authors.forename: Sergei P
authors.initials: SP
authors.lastname: Atamas
authors.forename: Irina G
authors.initials: IG
authors.lastname: Luzina
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hasday
authors.forename: Ju-Ren
authors.initials: JR
authors.lastname: He
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
authors.forename: Jacqueline J
authors.initials: JJ
authors.lastname: Coalson
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Yoder
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D000831:Animals, Newborn; D018932:Chemokine CCL2 / Q000032:analysis / Q000378:metabolism; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000032:analysis / Q000378:metabolism*; D008168:Lung / Q000737:chemistry / Q000382:microbiology / Q000473:pathology; D009130:Muscle, Smooth; D010215:Papio; D047928:Premature Birth / Q000382:microbiology* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D012121:Respiration, Artificial; D012141:Respiratory Tract Infections / Q000378:metabolism / Q000473:pathology; D051785:Smad Proteins / Q000032:analysis / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism; D016869:Ureaplasma Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016990:Ureaplasma urealyticum
chemical_list: D000199:Actins; D018932:Chemokine CCL2; D016207:Cytokines; D018836:Inflammation Mediators; D051785:Smad Proteins; D016212:Transforming Growth Factor beta