Mycobacterium abscessus is increasingly recognized as an important pathogen in some individuals with advancing lung disease related to cystic fibrosis (CF). Because of its resistance to antimicrobial agents and virulence, its presence in the lungs of potential lung transplant recipients can be problematic. We present 2 cases of individuals with CF in whom M. abscessus was present in the preoperative sputum cultures. The organism manifested different degrees of invasiveness in the 2 cases after transplantation with different outcomes, suggesting an approach to future candidates for lung transplantation that may be of clinical significance to their physicians and surgeons.

Exposure to particulate air pollution is associated with increased cardiopulmonary morbidity and mortality, although the pathogenic mechanisms are poorly understood. We previously demonstrated that particulate matter (PM) exposure triggers massive oxidative stress in vascular endothelial cells (ECs), resulting in the loss of EC integrity and lung vascular hyperpermeability. We investigated the protective role of hydrogen sulfide (H(2)S), an endogenous gaseous molecule present in the circulation, on PM-induced human lung EC barrier disruption and pulmonary inflammation. Alterations in EC monolayer permeability, as reflected by transendothelial electrical resistance (TER), the generation of reactive oxygen species (ROS), and murine pulmonary inflammatory responses, were studied after exposures to PM and NaSH, an H(2)S donor. Similar to N-acetyl cysteine (5 mM), NaSH (10 μM) significantly scavenged PM-induced EC ROS and inhibited the oxidative activation of p38 mitogen-activated protein kinase. Concurrent with these events, NaSH (10 μM) activated Akt, which helps maintain endothelial integrity. Both of these pathways contribute to the protective effect of H(2)S against PM-induced endothelial barrier dysfunction. Furthermore, NaSH (20 mg/kg) reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in bronchoalveolar lavage fluids in a murine model of PM-induced lung inflammation. These data suggest a potentially protective role for H(2)S in PM-induced inflammatory lung injury and vascular hyperpermeability.

Lung transplantation remains the only viable therapy for patients with end-stage lung disease. However, the full utilization of this strategy is severely compromised by a lack of donor lung availability. The vast majority of donor lungs available for transplantation are from individuals after brain death (BD). Unfortunately, the early autonomic storm that accompanies BD often results in neurogenic pulmonary edema (NPE), producing varying degrees of lung injury or leading to primary graft dysfunction after transplantation. We demonstrated that sphingosine 1-phosphate (S1P)/analogues, which are major barrier-enhancing agents, reduce vascular permeability via the S1P1 receptor, S1PR1. Because primary lung graft dysfunction is induced by lung vascular endothelial cell barrier dysfunction, we hypothesized that the S1PR1 agonist, SEW-2871, may attenuate NPE when administered to the donor shortly after BD. Significant lung injury was observed after BD, with increases of approximately 60% in bronchoalveolar lavage (BAL) total protein, cell counts, and lung tissue wet/dry (W/D) weight ratios. In contrast, rats receiving SEW-2871 (0.1 mg/kg) 15 minutes after BD and assessed after 4 hours exhibited significant lung protection (z 50% reduction, P ¼ 0.01), as reflected by reduced BAL protein/albumin, cytokines, cellularity, and lung tissue wet/dry weight ratio. Microarray analysis at 4 hours revealed a global impact of both BD and SEW on lung gene expression, with a differential gene expression of enriched immune-response/inflammation pathways across all groups. Overall, SEW served to attenuate the BD-mediated up-regulation of gene expression. Two potential biomarkers, TNF and chemokine CC motif receptor-like 2, exhibited gene array dysregulation. We conclude that SEW-2871 significantly attenuates BD-induced lung injury, and may serve as a potential candidate to improve human donor availability.Keywords: neurogenic pulmonary edema; lung injury; sphingosine 1-phosphate; sphingolipids; lung transplant donors Over the past decade, lung transplantation has become an increasingly important mode of therapy for patients with a variety of endstage lung diseases. The vast majority of lung donors are individuals with brain death (BD). However, the early autonomic storm accompanying brain BD triggers the development of systemic and pulmonary inflammatory responses, which lead to increased pulmonary endothelial permeability (1, 2) and to the sympathetic vasoconstriction of the systemic and pulmonary vasculature. These changes, in addition to possible ischemiareperfusion injury, disrupt the integrity of the alveolar capillary membrane, resulting in neurogenic pulmonary edema (NPE) (1-4). Increased pulmonary interstitial and alveolar fluid accumulation usually develops rapidly after acute injury to the central nervous system (1), and any preventive treatment should be given early after BD (3). This lung injury mimics a form of acute respiratory distress syndrome (ARDS), the most devastating form of acute lung injury (ALI), with excessive ...

The discovery of novel mediators in PAH allows for novel insights into PAH pathobiology and identification of therapeutic targets. PBMC expression profiles from 7 PAH patients (49±7 years, mPAP 55±18 mmHg, PVR 14±11 U) and 10 healthy controls (45±7 years) identified 224 differentially expressed genes including PBEF as an upregulated gene in PAH. We previously identified PBEF as a mediator in lung injury, with extracellular proinflammatory cytokine‐like activity and intracellular enzymatic activity regulating NAD levels, cell redox state, histone deacetylases and inhibiting apoptosis. Plasma PBEF levels were higher in PAH patients (n=10, 46±17 years, mPAP 56±18 mmHg, PVR 10±4 U) than controls (n=9, 33±7 years), (5000±2000 vs. 7500 ± 3000 pg/ml; P=0.04) and trended with BNP levels (R=0.6, P=0.08) and inversely with 6‐minute walk distance (R=−0.57, P=0.08). Immunohistochemistry in explanted PAH lungs (n=3) revealed significant PBEF expression in plexiform lesions and in remodeled PAs, without PBEF staining in PAs of controls. Finally, compared to WT control mice, PBEF heterozygous mice (PBEF+/−) developed less severe PH (FIO2=10% and SU5416 for 3 weeks) with less significant elevations in RVSP (PBEF+/+ 19 ± 2 vs. PBEF+/− 12 ± 4 mmHg, P=0.03) and less RVH (RV/LV+S: PBEF+/+ 0.44 ± 0.05 vs. PBEF+/− 0.34 ± 0.08, P=0.06). Our results implicate PBEF as a novel biomarker and therapeutic target in PAH.

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