Published ahead of print on June 30, 2005, doi:10.1164/rccm.200505-767OC Am. J. Respir. Crit. Care Med., Volume 172, Number 7, October 2005, 869-877 A more recent version of this article appeared on October 1, 2005
Submitted on May 16, 2005 Alveolar Surfactant Protein D Content Modulates Bleomycin Induced Lung InjuryJohn Casey1,1 Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA, 2 Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, 3 Division of Pulmonary Sciences and Critical Care Medicine, Denver Health Medical Center, Denver, CO, USA, 4 Department of Pediatrics and Division of Neonatology, University of California at San Francisco, San Francisco, CA, USA * To whom correspondence should be addressed. E-mail: mfbeers{at}mail.med.upenn.edu.
Rationale: Surfactant protein D (SP-D) is a collectin family member with demonstrated immunomodulatory properties in vitro. We hypothesized that SP-D modulates inflammation during non-infectious lung injury in vivo. Objectives: To investigate the association of alveolar SP-D and injury, we studied the responses of transgenic mice expressing varying levels of SP-D to intratracheal bleomycin (ITB). Methods: 8-week old C57/BL6 SP-D deficient (-/-) mice and syngeneic wild type (WT) controls or Swiss Black SP-D overexpressing (SP-D OE) mice and littermate controls received either ITB or saline and were followed for up to 21 days. Measurements and Results: Kaplan Meier analysis demonstrated a dose-dependent decrease in survival in ITB SP-D (-/-) mice receiving 2 U/kg bleomycin with a fourteen-day mortality of 100% versus 0% mortality for WT receiving 2 U/kg ITB or SP-D (-/-) mice given saline (p<0.05). At 8 days, ITB SP- (-/-) mice had greater respiratory distress (frequency / tidal volume) and weight loss than ITB WT mice. Furthermore, bronchoalveolar lavage cellularity, pulmonary parenchymal inflammation, and tissue 3-nitrotyrosine were increased to a greater extent in ITB SP-D (-/-) mice. By 21 days, compared with all groups, ITB SP-D (-/-) survivors had increased Trichrome staining and tissue hydroxyproline levels. As proof of principle, SP-D OE mice were highly resistant to bleomycin induced morbidity and mortality at doses up to 3U / kg. Conclusion: These data provide new in vivo evidence for an anti-inflammatory role for SP-D in response to non-infectious, subacute lung injury via modulation of oxidative-nitrative stress. Key words: Lung; Bleomycin; Innate Immunity; Collectins; Nitric Oxide
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