Genome-wide transcriptional profiling reveals connective tissue mast cell accumulation in bronchopulmonary dysplasia.

ABSTRACT

RATIONALE Bronchopulmonary dysplasia (BPD) is a major complication of premature birth. Risk factors for BPD are complex and include prenatal infection and O(2) toxicity. BPD pathology is equally complex and characterized by inflammation and dysmorphic airspaces and vasculature. Due to the limited availability of clinical samples, an understanding of the molecular pathogenesis of this disease and its causal mechanisms and associated biomarkers is limited. OBJECTIVES: Apply genome-wide expression profiling to define pathways affected in BPD lungs. METHODS: Lung tissue was obtained at autopsy from 11 BPD cases and 17 age-matched control subjects without BPD. RNA isolated from these tissue samples was interrogated using microarrays. Standard gene selection and pathway analysis methods were applied to the data set. Abnormal expression patterns were validated by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: We identified 159 genes differentially expressed in BPD tissues. Pathway analysis indicated previously appreciated (e.g., DNA damage regulation of cell cycle) as well as novel (e.g., B-cell development) biological functions were affected. Three of the five most highly induced genes were mast cell (MC)-specific markers. We confirmed an increased accumulation of connective tissue MC(TC) (chymase expressing) mast cells in BPD tissues. Increased expression of MC(TC) markers was also demonstrated in an animal model of BPD-like pathology. CONCLUSIONS: We present a unique genome-wide expression data set from human BPD lung tissue. Our data provide information on gene expression patterns associated with BPD and facilitated the discovery that MC(TC) accumulation is a prominent feature of this disease. These observations have significant clinical and mechanistic implications.