Role of SP-C in Familial Interstitial Lung Disease

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

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Abstract

DESCRIPTION (provided by applicant): The experimental aims of this grant are based upon the central hypothesis that insufficient levels of pulmonary surfactant protein C (SP-C) results in an inherited interstitial lung disease (ILD). Examples of familial ILD have been linked to either the absence of SP-C or expression of mutated forms of SP-C. The pathologic features of familial ILD are complex and variable. Identification of early events initiating the injury has been complicated by the diagnosis of ILD usually occurring after the disease is well established. We have used gene targeting to develop SP-C deficient (-/-) mice that develop a progressive injury similar to the complex human ILD/pulmonary fibrosis. The SP-C-/- mice are a novel model to investigate SP-C related familial ILD and will be used to determine requirements for early intervention to prevent or arrest disease progression (Aims 1 and 2) and to identify changes in gene expression and associated molecular pathways that occur at the onset of disease process (Aim 3). In Aim 1, the timing, levels, and cell specific requirements for SP-C replacement to alter ILD will be determined. Genetic restoration of SP-C in type II cells of SP-C-/- mice at discrete ages will be accomplished using inducible transgene technology. The SP-C-/- mice develop early indications of pulmonary inflammation and lipid imbalance, which includes lipid-filled macrophages and interstitial cells. SP-C stimulates surfactant lipid reutilization. Aim 2 will deliver exogenous SP-C preparations to lungs of very young SP-C-/- mice to determine if alveolar SP-C reverses the progressive lipidosis. Lipid pool sizes, cell infiltrates will be quantitated and cellular changes within the alveolar interstitium determined by electronmicroscopy. Inflammatory changes are detected in the lungs of young SP-C-/- mice. Experiments in Aim 3 will test the hypothesis that SP-C reduces LPS stimulation of alveolar cells to prevent inflammation. Final experiments will identify changes in type II cell gene expression associated with the loss of SP-C. The aims of this application focus on correction of early stages of developing ILD, and to identifying early cellular changes and changes in gene expression that could be targets for therapeutic intervention. The SP-C-/- mice provide a novel model of human interstitial disease where the inductive sequences of events remain undefined.