bromochloroacetic-acid and Bronchopulmonary-Dysplasia

Smoking during pregnancy increases the risk of bronchopulmonary dysplasia (BPD) and, in mice, gestational exposure to sidestream cigarette smoke (SS) induces BPD-like condition characterized by alveolar simplification, impaired angiogenesis, and suppressed surfactant protein production. Normal fetal development occurs in a hypoxic environment and nicotinic acetylcholine receptors (nAChRs) regulate the hypoxia-inducible factor (HIF)-1α that controls apoptosis and angiogenesis. To understand SS-induced BPD, we hypothesized that gestational SS affected alveolar development through HIF-1α.. Pregnant BALB/c mice were exposed to air (control) or SS throughout the gestational period and the 7-day-old lungs of the progeny were examined.. Gestational SS increased apoptosis of alveolar and airway epithelial cells. This response was associated with increased alveolar volumes, higher levels of proapoptotic factors (FOXO3a, HIPK2, p53, BIM, BIK, and BAX) and the antiangiogenic factor (GAX), and lower levels of antiapoptotic factors (Akt-PI3K, NF-κB, HIF-1α, and Bcl-2) in the lung. Although gestational SS increased the cells containing the proangiogenic bombesin-like-peptide, it markedly decreased the expression of its receptor GRPR in the lung. The effects of SS on apoptosis were attenuated by the nAChR antagonist mecamylamine.. Gestational SS-induced BPD is potentially regulated by nAChRs and associated with downregulation of HIF-1α, increased apoptosis of epithelial cells, and increased alveolar volumes. Thus, in mice, exposure to sidestream tobacco smoke during pregnancy promotes BPD-like condition that is potentially mediated through the nAChR/HIF-1α pathway.

Topics: Alveolar Epithelial Cells; Angiogenesis Inhibitors; Animals; Apoptosis; Apoptosis Regulatory Proteins; Bronchopulmonary Dysplasia; Caspase 3; Disease Models, Animal; Down-Regulation; Female; Hypoxia-Inducible Factor 1, alpha Subunit; Keratins; Maternal Exposure; Mecamylamine; Mice; NF-kappa B; Pregnancy; Respiratory Mucosa; Smoking

Bronchopulmonary dysplasia (BPD), a multifactorial disease of preterm neonates of complex etiology, is a significant problem within very low birth weight infants. Nitric oxide (NO) has been implicated in both the pathogenesis and as a potential therapeutic of this disease. At this time, there is little direct evidence of the changes in NO production and metabolism that occur within BPD in humans. Animal models have implied that reduced nitric oxide synthase (NOS) expression and NO production in the early stages of the disease may be critical factors. However, inflammation and hence iNOS expression, is also thought to play a role. In the present study we have utilized pathological samples to determine changes in the expression of NOS and NO metabolites within late stage BPD. It is our contention that within these samples iNOS expression is increased and associated with increased NO metabolite production. Mild immunostaining of all three nitric oxide synthase (NOS) enzymes (neuronal, inducible and endothelial) is observed in control lung with tight localization to the endothelium and epithelial airway. This tight localization was lost in samples from subjects with BPD. There was also a marked increase in iNOS expression throughout the lung tissue with strong coexistence with an epithelial cell marker cytokeratin. NO reaction products are altered with BPD as evidenced by increased S-nitrosothiol (SNO) and strong nitrotyrosine (NO(2)Y) imunoreactivity. This study demonstrates a strong correlation between products of NO reactivity and NOS localization in BPD.

Topics: Biomarkers; Bronchopulmonary Dysplasia; Epithelial Cells; Female; Gene Expression; Gestational Age; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Keratins; Male; Nitric Oxide; Nitric Oxide Synthase