Reversibility of lung inflammation caused by SP-B deficiency

• Published in: American journal of physiology. Lung cellular and molecular physiology 2005-12, Vol.289 (6), p.L962-L970
• Main Authors: Ikegami, Machiko, Whitsett, Jeffrey A, Martis, Prithy C, Weaver, Timothy E
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - administration & dosage; Cytokines - metabolism; Doxycycline - administration & dosage; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Humans; Infant, Newborn; L-Selectin - metabolism; Lung - metabolism; Lung - pathology; Macrophages, Alveolar - metabolism; Macrophages, Alveolar - pathology; Mice; Mice, Transgenic; Peptides - metabolism; Phospholipids - metabolism; Phosphorylation; Pneumonia - genetics; Pneumonia - metabolism; Pneumonia - pathology; Promoter Regions, Genetic - genetics; Pulmonary Surfactant-Associated Protein B - deficiency; Pulmonary Surfactant-Associated Protein B - genetics; Pulmonary Surfactant-Associated Protein B - metabolism; Respiratory Distress Syndrome, Newborn - genetics; Respiratory Distress Syndrome, Newborn - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; STAT3 Transcription Factor - metabolism; Uteroglobin - genetics; Uteroglobin - metabolism
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00214.2005

Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio Submitted 17 May 2005 ; accepted in final form 11 July 2005 Whereas decreased concentrations of surfactant protein (SP)-B are associated with lung injury and respiratory distress, potential causal relationships between SP-B deficiency and lung inflammation remain unclear. A transgenic mouse in which human SP-B expression was placed under conditional control of doxycycline via the CCSP promoter was utilized to determine the role of SP-B in the initiation of pulmonary inflammation. Adult mice, made SP-B deficient by removal of doxycycline, developed severe respiratory failure within 4 days. Deficiency of SP-B was associated with increased minimal surface tension of the surfactant and perturbed lung mechanics. Four days of SP-B deficiency did not alter SP-C content or surfactant phospholipid content or composition. SP-B deficiency was associated with lung inflammation and increased soluble L-selectin, STAT-3, and phosphorylated STAT-3 in alveolar macrophages and alveolar epithelial cells. Alveolar IL-6, IL-1 , and macrophage inflammatory protein-2 concentrations were increased after removal of doxycycline, indicating pulmonary inflammation. Restoration of SP-B expression following administration of doxycycline rapidly reversed SP-B-dependent abnormalities in lung mechanics and inflammation. SP-B deficiency is sufficient to cause lung dysfunction and inflammation in adult mice. SP-B reversed inflammation and maintained lung function in vivo, indicating its potential utility for the prevention and treatment of pulmonary injury and surfactant deficiency. pulmonary surfactant; surfactant proteins; lung injury; L-selectin; cytokines Address for reprint requests and other correspondence: M. Ikegami, Cincinnati Children's Hospital Medical Center, Div. of Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039 (e-mail: machiko.ikegami{at}cchmc.org )