Publications

Prevention or treatment of lung diseases caused by the failure to form, or destruction of, existing alveoli, as observed in infants with bronchopulmonary dysplasia and adults with emphysema, requires understanding of the molecular mechanisms of alveolar development. In addition to its critical role in gas exchange, the pulmonary circulation also contributes to alveolar morphogenesis and maintenance by the production of paracrine factors, termed "angiocrines," that impact the development of surrounding tissue. To identify lung angiocrines that contribute to alveolar formation, we disrupted pulmonary vascular development by conditional inactivation of the Vegf-A gene during alveologenesis. This resulted in decreased pulmonary capillary and alveolar development and altered lung elastin and retinoic acid (RA) expression. We determined that RA is produced by pulmonary endothelial cells and regulates pulmonary angiogenesis and elastin synthesis by induction of VEGF-A and fibroblast growth factor (FGF)-18, respectively. Inhibition of RA synthesis in newborn mice decreased FGF-18 and elastin expression and impaired alveolarization. Treatment with RA and vitamin A partially reversed the impaired vascular and alveolar development induced by VEGF inhibition. Thus we identified RA as a lung angiocrine that regulates alveolarization through autocrine regulation of endothelial development and paracrine regulation of elastin synthesis via induction of FGF-18 in mesenchymal cells.

Background.  Morbidity and mortality remain high among hospitalized patients infected with human immunodeficiency virus (HIV) in sub-Saharan Africa despite widespread availability of antiretroviral therapy. Severe anemia is likely one important driver, and some evidence suggests that blood transfusions may accelerate HIV progression and paradoxically increase short-term mortality. We investigated the relationship between anemia, blood transfusions, and mortality in a South African district hospital. Methods.  Unselected consecutive HIV-infected adults requiring acute medical admission to a Cape Town township district hospital were recruited. Admission hemoglobin concentrations were used to classify anemia severity according to World Health Organization/AIDS Clinical Trials Group criteria. Vital status was determined at 90 days, and Cox regression analyses were used to determine independent predictors of mortality. Results.  Of 585 HIV-infected patients enrolled, 578 (98.8%) were included in the analysis. Anemia was detected in 84.8% of patients and was severe (hemoglobin, 6.5-7.9 g/dL) or life-threatening (hemoglobin, <6.5 g/dL) in 17.3% and 13.3%, respectively. Within 90 days of the date of admission, 13.5% (n = 78) patients received at least 1 blood transfusion with red cell concentrate and 77 (13.3%) patients died. In univariable analysis, baseline hemoglobin and receipt of blood transfusion were associated with increased mortality risk. However, in multivariable analysis, neither hemoglobin nor receipt of a blood transfusion were independently associated with greater mortality risk. Acquired immune deficiency syndrome-defining illnesses other than tuberculosis and impaired renal function independently predicted mortality. Conclusions.  Newly admitted HIV-infected adults had a high prevalence of severe or life-threatening anemia and blood transfusions were frequently required. However, after adjustment for confounders, blood transfusions did not confer an increased mortality risk.