Hypoxia-induced mitogenic factor (FIZZ1/RELMα) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension.

Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right heart failure and ultimately death. Injury to endothelium and consequent wound repair cascades have been suggested to trigger pulmonary vascular remodeling, such as that observed during PH. The relationship between injury to endothelium and disease pathogenesis in this disorder remains poorly understood. We and others have shown that, in mice, hypoxia-induced mitogenic factor (HIMF, also known as FIZZ1 or RELMα) plays a critical role in the pathogenesis of lung inflammation and the development of PH. In this study, we dissected the mechanism by which HIMF and its human homolog resistin (hRETN) induce pulmonary endothelial cell (EC) apoptosis and subsequent lung inflammation-mediated PH, which exhibits many of the hallmarks of the human disease. Systemic administration of HIMF caused increases in EC apoptosis and interleukin (IL)-4-dependent vascular inflammatory marker expression in mouse lung during the early inflammation phase. In vitro, HIMF, hRETN, and IL-4 activated pulmonary microvascular ECs (PMVECs) by increasing angiopoietin-2 expression and induced PMVEC apoptosis. In addition, the conditioned medium from hRETN-treated ECs had elevated levels of endothelin-1 and caused significant increases in pulmonary vascular smooth muscle cell proliferation. Last, HIMF treatment caused development of PH that was characterized by pulmonary vascular remodeling and right heart failure in wild-type mice but not in IL-4 knockout mice. These data suggest that HIMF contributes to activation of vascular inflammation at least in part by inducing EC apoptosis in the lung. These events lead to subsequent PH.

A systematic approach for developing a ventilator-associated pneumonia prevention bundle.

BACKGROUND: Ventilator-associated pneumonia (VAP) is among the most common type of health care-associated infection in the intensive care unit and is associated with significant morbidity and mortality. Existing VAP prevention intervention bundles vary widely on the interventions included and in the approaches used to develop these bundles. The objective of this study was to develop a new VAP prevention bundle using a systematic approach that elicits clinician perceptions on which interventions are most important and feasible to implement. METHODS: We identified potential interventions to include through a review of current guidelines and literature. We implemented a 2-step modified Delphi method to gain consensus on the final list of interventions. An interdisciplinary group of clinical experts participated in the Delphi process, which was guided by a technical expert panel. RESULTS: We identified 65 possible interventions. Through the Delphi method, we narrowed that list to 19 interventions that included 5 process and 14 structural measures. CONCLUSIONS: We described a structured approach for developing a new VAP prevention bundle. Obtaining clinician input on what interventions to include increases the likelihood that providers will adhere to the bundle.