Anti-transforming growth factor-beta monoclonal antibodies prevent lung injury in hemorrhaged mice.
Acute lung injury, characterized as the adult respiratory distress syndrome (ARDS), is a common clinical occurrence following blood loss and injury. We previously found increased levels of transforming growth factor (TGF)-beta 1 mRNA in murine intraparenchymal mononuclear cells and in alveolar macrophages within 1 h after hemorrhage. Because TGF-beta has potent proinflammatory and immunoregulatory properties, we investigated the effect of blocking TGF-beta with mAb on hemorrhage-induced pathology, cytokine mRNA levels in lungs, as well as survival from pneumonia. Mice treated with anti-TGF-beta mAb showed normal pulmonary histology 3 days after hemorrhage and resuscitation in contrast to the mononuclear and neutrophil infiltrates, intraalveolar hemorrhage, and interstitial edema found in hemorrhaged mice either treated with control antibody or not treated with any antibody. Decreased mRNA levels for IL-1 beta, TNF-alpha, IL-6, IL-10, and IFN-gamma as compared with untreated, hemorrhaged controls were present in intraparenchymal pulmonary mononuclear cells following therapy with anti-TGF-beta. In contrast, therapy with anti-TGF-beta increased mRNA levels for IL-1 beta and TNF-alpha in alveolar macrophages and for TGF-beta in peripheral blood mononuclear cells collected 3 days after hemorrhage. Administration of anti-TGF-beta to hemorrhaged mice did not correct the enhanced susceptibility to Pseudomonas aeruginosa pneumonia that exists after hemorrhage. These results suggest that TGF-beta has an important role in hemorrhage-induced acute lung injury, but does not contribute to the post-hemorrhage depression in pulmonary antibacterial response.
Shenkar
R
R
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver 80262.
Coulson
W F
WF
Abraham
E
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006470:Hemorrhage / Q000150:complications*; D007963:Leukocytes, Mononuclear / Q000737:chemistry; D008168:Lung / Q000473:pathology; D016676:Macrophages, Alveolar / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000737:chemistry; D011014:Pneumonia / Q000628:therapy; D011552:Pseudomonas Infections / Q000628:therapy; D012333:RNA, Messenger / Q000032:analysis; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D012151:Resuscitation; D016212:Transforming Growth Factor beta / Q000276:immunology*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta