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.

Sources of Methodological Variability in Phase Angles from Respiratory Inductance Plethysmography in Preterm Infants

“…We were able to use more than 50 breaths in 55 of 65 subjects. Furthermore, Figure 7 suggests that counting more than 50 breaths in sessions of similar duration in the majority of infants would not change the results in an important way, e.g., mean F difference by .20 8 . The optimal number of breaths for fine distinctions was not explored, but it seems unlikely that RIP will be used for such comparisons (e.g., suggesting that differences in F as small as 10 8 or 20 8 indicate important physiological differences).…”

“…At V f of 40 breaths per minute, mean F = 126.1 6 1.4 8 . At V f of 60 breaths per minute, mean F = 64.6 6 1.5 8 . Coefficients of variation were 1.1% and 2.3%, respectively.…”

“…This evaluation was conducted at Washington University School of Medicine and St. Louis Children's Hospital as a singlecenter study within a larger multicenter collaboration (Premature Respiratory Outcome Program [PROP]) (8,9). The study protocol was reviewed and approved by the Washington University Human Research Protection Office and the PROP Observational Studies Monitoring Board.…”

“…In a previous study, F was found to be 9-12 8 in healthy term infants, 38-60 8 in healthy preterm infants at 35-36 weeks PMA, and 70 8 or more in older infants with bronchopulmonary dysplasia (7). We therefore are using RIP as part of a large multicenter study in an attempt to quantify respiratory mechanics noninvasively in premature infants.…”

Effects of intra-amniotic lipopolysaccharide exposure on the fetal lamb lung as gestation advances

“…The relationship between prenatal inflammation and the mast cell response in the fetal airways has not been studied. Increased levels of mast cells were associated with the development of BPD in one autopsy study (30). Mast cell regulation is complex, depending on the timing of the fetal and postnatal stimuli.…”