SP-D in pulmonary remodeling

Children'S Hospital Med Ctr (Cincinnati), Cincinnati OH

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Abstract

(Applicant's Abstract) This application will determine the role of pulmonary surfactant protein D (SP-D) in the modulation of pulmonary inflammation and maintenance of postnatal alveolar structure. SP-D is a member of the collectin family of host defense molecules expressed in various tissues, but at highest levels in the lung where it plays a role in innate immunity. SP-D binds various pathogenic microbes, enhancing phagocytosis, and modulating inflammation. Recently, decreased or absent levels of SP-D were detected in BALF from patients with CF and RSV pneumonia providing a strong inference that decreased SP-D may contribute to lung inflammation. The investigators recently developed mice lacking SP-D by targeted gene inactivation (SP-D -/-) and demonstrated increased pro-inflammatory cytokines and inflammatory cell influx following intranasal or intratracheal instillation of respiratory syncytial virus (RSV) and influenza virus A. SP-D (-/-) mice developed pulmonary inflammation and enlarged alveoli following neonatal RSV infection at 4 days of age. In the absence of RSV, lung development was normal, until 3 weeks of age when SP-D (-/-) mice spontaneously developed pulmonary inflammation and emphysema, demonstrating that lack of SP-D contributes to abnormal alveolar remodeling. Thus, the present application will test the central hypothesis that SP-D plays a critical role in modulation of lung inflammation and protection against pulmonary injury following RSV infection of the postnatal developing lung. To test the hypothesis, Aim 1 will determine the role of SP-D in the modulation of RSV induced pulmonary inflammation and airway remodeling in neonatal and postnatal mouse lungs. Aim 2 will determine whether SP-D regulates the balance of proteinases/antiproteinases that the investigators hypothesize underlies the pathogenesis of abnormal alveolar formation in the SP-D (-/-) mice by testing whether SP-D regulates metalloproteinases (NMP) -9, -2, and -12. Aim 3 will determine whether mutations in specific domains of SP-D contribute to or ameliorate neonatal lung inflammation and airway remodeling in mice or in conjunction with the Clinical Core, in infants with chronic lung disease. This SCOR project will clarify the role of SP-D in modulating pulmonary inflammatory responses and alveolar remodeling and may provide scientific support for the use of SP-D in treatment of chronic lung diseases of children, e.g. bronchopulmonary dysplasia.