Pannexin-1 channels on endothelial cells mediate vascular inflammation during lung ischemia-reperfusion injury.

Ischemia-reperfusion (I/R) injury (IRI), which involves inflammation, vascular permeability, and edema, remains a major challenge after lung transplantation. Pannexin-1 (Panx1) channels modulate cellular ATP release during inflammation. This study tests the hypothesis that endothelial Panx1 is a key mediator of vascular inflammation and edema after I/R and that IRI can be blocked by Panx1 antagonism. A murine hilar ligation model of IRI was used whereby left lungs underwent 1 h of ischemia and 2 h of reperfusion. Treatment of wild-type mice with Panx1 inhibitors (carbenoxolone or probenecid) significantly attenuated I/R-induced pulmonary dysfunction, edema, cytokine production, and neutrophil infiltration versus vehicle-treated mice. In addition, VE-Cad-CreERT2+/Panx1fl/fl mice (tamoxifen-inducible deletion of Panx1 in vascular endothelium) treated with tamoxifen were significantly protected from IRI (reduced dysfunction, endothelial permeability, edema, proinflammatory cytokines, and neutrophil infiltration) versus vehicle-treated mice. Furthermore, extracellular ATP levels in bronchoalveolar lavage fluid is Panx1-mediated after I/R as it was markedly attenuated by Panx1 antagonism in wild-type mice and by endothelial-specific Panx1 deficiency. Panx1 gene expression in lungs after I/R was also significantly elevated compared with sham. In vitro experiments demonstrated that TNF-α and/or hypoxia-reoxygenation induced ATP release from lung microvascular endothelial cells, which was attenuated by Panx1 inhibitors. This study is the first, to our knowledge, to demonstrate that endothelial Panx1 plays a key role in mediating vascular permeability, inflammation, edema, leukocyte infiltration, and lung dysfunction after I/R. Pharmacological antagonism of Panx1 activity may be a novel therapeutic strategy to prevent IRI and primary graft dysfunction after lung transplantation.

A 30-year analysis of National Institutes of Health-funded cardiac transplantation research: Surgeons lead the way.

OBJECTIVES: Obtaining National Institutes of Health funding for heart transplant research is becoming increasingly difficult, especially for surgeons. We sought to determine the impact of National Institutes of Health-funded cardiac transplantation research over the past 30 years. METHODS: National Institutes of Health Research Portfolio Online Reporting Tools Expenditures and Results was queried for R01s using 10 heart transplant-related terms. Principal Investigator, total grant funding amount, number of publications, and citations of manuscripts were collected. A citation-based Grant Impact Metric was assigned to each grant: sum of citations for each manuscript normalized by the funding of the respective grant (per $100K). The department and background degree(s) (MD, PhD, MD/PhD) for each funded Principal Investigator were identified from institutional faculty profiles. RESULTS: A total of 321 cardiac transplantation R01s totaling $723 million and resulting in 6513 publications were analyzed. Surgery departments received more grants and more funding dollars to study cardiac transplantation than any other department (n = 115, $249 million; Medicine: n = 93, $208 million; Pathology: 26, $55 million). Surgeons performed equally well compared with all other Principal Investigators with respect to Grant Impact Metric (15.1 vs 20.6; P = .19) and publications per $1 million (7.5 vs 6.8; P = .75). Finally, all physician-scientists (MDs) have a significantly higher Grant Impact Metric compared with nonclinician researchers (non-MDs) (22.3 vs 16.3; P = .028). CONCLUSIONS: Surgeon-scientists are equally productive and impactful compared with nonsurgeons despite decreasing funding rates at the National Institutes of Health and greater pressure from administrators to increase clinical productivity.

Cardiothoracic and Vascular Surgeons Achieve High Rates of K Award Conversion Into R01 Funding.

BACKGROUND: Obtaining National Institutes of Health (NIH) R01 funding remains extremely difficult. The utility of career development grants (K awards) for achieving the goal of R01 funding remains debated, particularly for surgeon-scientists. We examined the success rate for cardiothoracic and vascular (CTV) surgeons compared with other specialties in converting K-level grants into R01 equivalents. METHODS: All K (K08 and K23) grants awarded to surgeons by the NIH between 1992 and 2017 were identified through NIH Research Portfolio Online Report Tools (RePORTER), an online database combining funding, publications, and patents. Only grants awarded to CTV surgeons were included. Grants active within the past year were excluded. Mann-Whitney U tests and χ2 tests were used to compare groups. RESULTS: During this period, 62 K grants were awarded to CTV surgeons. The analysis excluded 16 grants that were still active within the last year. Twenty-two (48%) of the remaining K awardees successfully transitioned to an R01 or equivalent grant. Awardees with successful conversion published nine publications per K grant compared with four publications for those who did not convert successfully (p = 0.01). The median time for successful conversion to an R grant was 5.0 years after the K award start date. Importantly, the 10-year conversion rate to R01 was equal for CTV surgeons compared with other clinician-investigators (52.6% vs 42.5%). CONCLUSIONS: CTV surgeons have an equal 10-year conversion rate to the first R01 award compared with other clinicians. These data suggest that NIH achieves a good return on investment when funding CTV surgeon-scientists with K-level funding.

Surgeon Scientists Are Disproportionately Affected by Declining NIH Funding Rates.

BACKGROUND: Obtaining National Institutes of Health (NIH) funding over the last 10 years has become increasingly difficult due to a decrease in the number of research grants funded and an increase in the number of NIH applications. STUDY DESIGN: National Institutes of Health funding amounts and success rates were compared for all disciplines using data from NIH, Federation of American Societies for Experimental Biology (FASEB), and Blue Ridge Medical Institute. Next, all NIH grants (2006 to 2016) with surgeons as principal investigators were identified using the National Institutes of Health Research Portfolio Online Reporting Tools Expenditures and Results (NIH RePORTER), and a grant impact score was calculated for each grant based on the publication's impact factor per funding amount. Linear regression and one-way ANOVA were used for analysis. RESULTS: The number of NIH grant applications has increased by 18.7% (p = 0.0009), while the numbers of funded grants (p < 0.0001) and R01s (p < 0.0001) across the NIH have decreased by 6.7% and 17.0%, respectively. The mean success rate of funded grants with surgeons as principal investigators (16.4%) has been significantly lower than the mean NIH funding rate (19.2%) (p = 0.011). Despite receiving only 831 R01s during this time period, surgeon scientists were highly productive, with an average grant impact score of 4.9 per $100,000, which increased over the last 10 years (0.15 ± 0.05/year, p = 0.02). Additionally, the rate of conversion of surgeon scientist-mentored K awards to R01s from 2007 to 2012 was 46%. CONCLUSIONS: Despite declining funding over the last 10 years, surgeon scientists have demonstrated increasing productivity as measured by impactful publications and higher success rates in converting early investigator awards to R01s.