Reversibility of lung inflammation caused by SP-B deficiency.
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-1beta, 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.
Ikegami
Machiko
M
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. machiko.ikegami@cchmc.org
Whitsett
Jeffrey A
JA
Martis
Prithy C
PC
Weaver
Timothy E
TE
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D016207:Cytokines / Q000378:metabolism; D004318:Doxycycline / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins; D019041:L-Selectin / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D037701:Pulmonary Surfactant-Associated Protein B / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism
D000900:Anti-Bacterial Agents; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010743:Phospholipids; D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C; C556389:SCGB1A1 protein, human; D050796:STAT3 Transcription Factor; C556390:Scgb1a1 protein, mouse; C489680:Sftpc protein, mouse; C494087:Stat3 protein, mouse; D019041:L-Selectin; D014598:Uteroglobin; D004318:Doxycycline