Keshavjee, Shaf

ABSTRACTLung transplantation is indicated for selected patients with advanced pulmonary arterial hypertension (PAH). We used a modified Delphi process to develop recommendations on care of patients with PAH undergoing lung transplantation. This Delphi panel was recruited from the Pulmonary Vascular Research Institute's Innovative Drug Discovery Initiative ‐ Lung Transplantation Workstream, consisting of clinical and research experts in PAH and lung transplantation. In this process, 29 panelists were given open‐ended questions, querying topics related to lung transplantation in PAH. A steering group converted the responses into discrete statements. Panelists then rated agreement using a Likert scale in two further survey rounds: −5 (strongly disagree) to 5 (strongly agree). Consensus was defined as mean ≥ 2.5 or ≤ −2.5, with a standard deviation not crossing zero. Consensus was reached on 141 of 223 statements. Notable areas of consensus were for early discussions about transplantation, and agreement with previously published referral and listing criteria. There was agreement that lung transplantation could be offered in sick candidates, including those with concurrent renal or hepatic insufficiency. Bilateral lung transplantation was considered the procedure of choice for most patients, with rare indications for heart‐lung transplantation. Consensus on bridging strategies included use of veno‐arterial extracorporeal membrane oxygenation and preemptive awake cannulation in those with severe right ventricular dysfunction. Consensus was also achieved on intraoperative use of invasive hemodynamic monitoring, and prolonged postoperative circulatory support guided by hemodynamic response and echocardiography. Patients with PAH undergoing transplantation require specialized management, which differs somewhat from other candidates.

Recent evidence suggests that alveolar epithelial cells (AECs) may contribute to the development, propagation, and resolution of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Proinflammatory cytokines, pathogen products, and injurious mechanical ventilation are important contributors of excessive inflammatory responses in the lung. In the present study, we used cDNA microarrays to define the gene expression patterns of A549 cells (an AEC line) in the early stages of three models of pulmonary parenchymal cell activation: cells treated with tumor necrosis factor-α (TNFα) (20 ng/ml), lipopolysaccharide (LPS, 1 μg/ml), or cyclic stretch (20% elongation) for either 1 h or 4 h. Differential gene expression profiles were determined by gene array analysis. TNFα induced an inflammatory response pattern, including induction of genes for chemokines, inflammatory mediators, and cell surface membrane proteins. TNFα also increased genes related to pro- and anti-apoptotic proteins, signal transduction proteins, and transcriptional factors. TNFα further induced a group of genes that may form a negative feedback loop to silence the NFκB pathway. Stimulation of AECs with mechanical stretch changed cell morphology and activated Src protein tyrosine kinase. The combination of TNFα plus stretch enhanced or attenuated expression of multiple genes. LPS decreased microfilament polymerization but had less impact on NFκB translocation and gene expression. Results from this study indicate that AECs can tailor their response to different stimuli or/and combination of stimuli and subsequently play an important role in acute inflammatory responses in the lung.