Machine Learning-based Analysis of Publications Funded by the National Institutes of Health's Initial COVID-19 Pandemic Response.

Background: The National Institutes of Health (NIH) mobilized more than $4 billion in extramural funding for the COVID-19 pandemic. Assessing the research output from this effort is crucial to understanding how the scientific community leveraged federal funding and responded to this public health crisis. Methods: NIH-funded COVID-19 grants awarded between January 2020 and December 2021 were identified from NIH Research Portfolio Online Reporting Tools Expenditures and Results using the "COVID-19 Response" filter. PubMed identifications of publications under these grants were collected and the NIH iCite tool was used to determine citation counts and focus (eg, clinical, animal). iCite and the NIH's LitCOVID database were used to identify publications directly related to COVID-19. Publication titles and Medical Subject Heading terms were used as inputs to a machine learning-based model built to identify common topics/themes within the publications. Results and Conclusions: We evaluated 2401 grants that resulted in 14 654 publications. The majority of these papers were published in peer-reviewed journals, though 483 were published to preprint servers. In total, 2764 (19%) papers were directly related to COVID-19 and generated 252 029 citations. These papers were mostly clinically focused (62%), followed by cell/molecular (32%), and animal focused (6%). Roughly 60% of preprint publications were cell/molecular-focused, compared with 26% of nonpreprint publications. The machine learning-based model identified the top 3 research topics to be clinical trials and outcomes research (8.5% of papers), coronavirus-related heart and lung damage (7.3%), and COVID-19 transmission/epidemiology (7.2%). This study provides key insights regarding how researchers leveraged federal funding to study the COVID-19 pandemic during its initial phase.

Analysis of National Institutes of Health Funding for the COVID-19 Pandemic.

Background: Evaluating the National Institute's Health's (NIH's) response to the coronavirus disease 2019 (COVID-19) pandemic via grants and clinical trials is crucial to determining the impact they had on aiding US citizens. We determined how the NIH's funding for COVID-19 research was disbursed and used by various institutions across the United States. Methods: We queried NIH RePORTER and isolated COVID-19-related grants from January 2020 to December 2021. We analyzed grant type, geographical location, and awardee institution. Manuscripts published from these grants were quantitatively analyzed. COVID-19 clinical trials were mapped and distances from counties to clinical trial sites were calculated using ArcGis. Results: A total of 2401 COVID-19 NIH grants resulted in 14 654 manuscripts from $4.2 billion and generated more than 150 000 citations. R01s make up 32% of grants (763/2401) and 8% of funding ($329 million). UM1 grants account for the majority of funding (30.8%; $1.3 Billion). Five states received 50.6% of funding: North Carolina, Washington, New York, California, and Massachusetts. Finally, of the 1806 clinical trials across 1266 sites in the United States, the majority were in metropolitan areas in close proximity to areas of high COVID-19 disease burden. Conclusions and Relevance: Evaluating the outcome of the NIH's response to the COVID-19 pandemic is of interest to the general public. The present study finds that the NIH disbursed more than $4 billion in funding to large consortiums and clinical trials to develop diagnostics, therapeutics, and vaccines. Approximately 8% of funding was used for R01 grants. Clinical trial sites were generally located in areas of high COVID-19 burden.

A Nationwide Evaluation of Cardiothoracic Resident Research Productivity.

BACKGROUND: Evaluating the research productivity of cardiothoracic surgery residents during their training and early career is crucial for tracking their academic development. To this end, the training pathway of residents and the characteristics of their program in relation to their productivity were evaluated. METHODS: Alumni lists from integrated 6-year thoracic surgery (I-6) and traditional thoracic surgery residency programs were collected. A Python script was used to search PubMed for publications and the iCite database for citations from each trainee. Publications during a 20-year time span were stratified by the year of publication in relation to the trainee's graduation from thoracic surgery residency. Trainees were analyzed by training program type, institutional availability of a cardiothoracic surgery T32 training grant, and protected academic development time. RESULTS: A total of 741 cardiothoracic surgery graduates (I-6, 70; traditional, 671) spanning 1971 to 2021 from 57 programs published >23,000 manuscripts. I-6 trainees published significantly more manuscripts during medical school and residency compared with traditional trainees. Trainees at institutions with cardiothoracic surgery T32 training grants published significantly more manuscripts than those at non-T32 institutions (13 vs 9; P = .0048). I-6 trainees published more manuscripts at programs with dedicated academic development time compared with trainees at programs without protected time (22 vs 9; P = .004). CONCLUSIONS: I-6 trainees publish significantly more manuscripts during medical school and residency compared with their traditional colleagues. Trainees at institutions with T32 training grants and dedicated academic development time publish a higher number of manuscripts than trainees without those opportunities.

Effect of Cardiopulmonary Bypass on SARS-CoV-2 Vaccination Antibody Levels.

Background Adults undergoing heart surgery are particularly vulnerable to respiratory complications, including COVID-19. Immunization can significantly reduce this risk; however, the effect of cardiopulmonary bypass (CPB) on immunization status is unknown. We sought to evaluate the effect of CPB on COVID-19 vaccination antibody concentration after cardiac surgery. Methods and Results This prospective observational clinical trial evaluated adult participants undergoing cardiac surgery requiring CPB at a single institution. All participants received a full primary COVID-19 vaccination series before CPB. SARS-CoV-2 spike protein-specific antibody concentrations were measured before CPB (pre-CPB measurement), 24 hours following CPB (postoperative day 1 measurement), and approximately 1 month following their procedure. Relationships between demographic or surgical variables and change in antibody concentration were assessed via linear regression. A total of 77 participants were enrolled in the study and underwent surgery. Among all participants, mean antibody concentration was significantly decreased on postoperative day 1, relative to pre-CPB levels (-2091 AU/mL, P<0.001). Antibody concentration increased between postoperative day 1and 1 month post CPB measurement (2465 AU/mL, P=0.015). Importantly, no significant difference was observed between pre-CPB and 1 month post CPB concentrations (P=0.983). Two participants (2.63%) developed symptomatic COVID-19 pneumonia postoperatively; 1 case of postoperative COVID-19 pneumonia resulted in mortality (1.3%). Conclusions COVID-19 vaccine antibody concentrations were significantly reduced in the short-term following CPB but returned to pre-CPB levels within 1 month. One case of postoperative COVID 19 pneumonia-specific mortality was observed. These findings suggest the need for heightened precautions in the perioperative period for cardiac surgery patients.

Postdoctoral National Institutes of Health F32 Grants: Broken Pipeline in the Development of Surgeon-Scientists.

OBJECTIVE: We examined trainees in surgery and internal medicine who received National Institutes of Health (NIH) F32 postdoctoral awards to determine their success rates in obtaining future NIH funding. BACKGROUND: Trainees participate in dedicated research years during residency (surgery) and fellowship (internal medicine). They can obtain an NIH F32 grant to fund their research time and have structured mentorship. METHODS: We collected NIH F32 grants (1992-2021) for Surgery Departments and Internal Medicine Departments from NIH RePORTER, an online database of NIH grants. Nonsurgeons and noninternal medicine physicians were excluded. We collected demographic information on each recipient, including gender, current specialty, leadership positions, graduate degrees, and any future NIH grants they received. A Mann-Whitney U test was used for continuous variables, and a χ 2 test was utilized to analyze categorical variables. An alpha value of 0.05 was used to determine significance. RESULTS: We identified 269 surgeons and 735 internal medicine trainees who received F32 grants. A total of 48 surgeons (17.8%) and 339 internal medicine trainees (50.2%) received future NIH funding ( P < 0.0001). Similarly, 24 surgeons (8.9%) and 145 internal medicine trainees (19.7%) received an R01 in the future ( P < 0.0001). Surgeons who received F32 grants were more likely to be department chair or division chiefs ( P =0.0055 and P < 0.0001). CONCLUSIONS: Surgery trainees who obtain NIH F32 grants during dedicated research years are less likely to receive any form of NIH funding in the future compared with their internal medicine colleagues who received F32 grants.

Fewer Than One in 20 Current Academic Orthopaedic Surgeons Have Obtained National Institutes of Health Funding.

BACKGROUND: National Institutes of Health (NIH) funding is a key driver of orthopaedic research, but it has become increasingly difficult to obtain in recent years. An understanding of the types of grants that are commonly funded, how productive they are, and the factors associated with obtaining funding may help orthopaedic surgeons better understand how to earn grants. QUESTIONS/PURPOSES: In this study, we sought to determine (1) the proportion of current academic orthopaedic surgeons who have obtained NIH grant funding, (2) the productivity of these grants by calculating grant productivity metrics, and (3) the factors (such as gender, subspecialty, and additional degrees) that are associated with obtaining grant funding. METHODS: Current academic orthopaedic surgeons at the top 140 NIH-funded institutions were identified via faculty webpages; 3829 surgeons were identified. Demographic information including gender (men constituted 88% of the group [3364 of 3829]), academic rank (full professors constituted 22% [856 of 3829]), additional degrees (those with MD-PhD degrees constituted 3% [121 of 3829]), leadership positions, and orthopaedic subspecialty was collected. Funding histories from 1985 through 2021 were collected using the NIH Research Portfolio Online Reporting Tools Expenditures and Results. Grant type, funding, publications, and citations of each article were collected. A previously used grant impact metric (total citations per USD 0.1 million) was calculated to assess grant productivity. Multivariable binomial logistic regression was used to evaluate factors associated with obtaining funding. RESULTS: Four percent (150 of 3829) of academic orthopaedic surgeons obtained USD 338.3 million in funding across 301 grants, resulting in 2887 publications over the entire study period. The R01 was the most commonly awarded grant in terms of the total number awarded, at 36% (108 of 301), as well as by funding, publications, and citations, although other grant types including T32, F32, R03, R13, and R21 had higher mean grant impact metrics. There was no difference between men and women in the by-gender percentage of academic orthopaedic surgeons who obtained funding (4% [135 of 3229] versus 3% [15 of 450]; odds ratio 0.9 [95% confidence interval 0.5 to 1.7]; p = 0.80). A department having a single funded PhD researcher may be associated with surgeon-scientists obtaining grant funding, but with the numbers available, we could not demonstrate this was the case (OR 1.4 [95% CI 0.9 to 2.2]; p = 0.12). CONCLUSION: Fewer than one in 20 academic orthopaedic surgeons have received NIH funding. R01s are the most commonly awarded grant, although others demonstrate increased productivity metrics. Future studies should investigate the role of co-principal investigators on productivity and the role of different funding sources. CLINICAL RELEVANCE: Individuals should pursue both R01 and non-R01 grants, and departments should consider cultivating relationships with funded PhDs. The specific research infrastructure and departmental policies of the most productive institutions and grants should be surveyed and emulated.

The impact of the American Association for Thoracic Surgery on National Institutes of Health grant funding for cardiothoracic surgeons.

OBJECTIVES: The American Association for Thoracic Surgery, through its annual meeting, pilot grant funding, Scientific Affairs and Government Relations Committee activity, and academic development programs (Grant Writing Workshop, Clinical Trials Course, Innovation Summit), has aimed to develop the research careers of cardiothoracic surgeons. We hypothesized that American Association for Thoracic Surgery activities have helped increase National Institutes of Health grants awarded to cardiothoracic surgeons. METHODS: A database of 1869 academic cardiothoracic surgeons in the United States was created in December 2020. National Institutes of Health grant records from 1985 to 2020 were obtained for each surgeon using National Institutes of Health Research Portfolio Online Reporting Tools Expenditures and Results. Analyses were normalized to the number of active surgeons per year, based on the year of each surgeon's earliest research publication on Scopus. RESULTS: A total of 346 cardiothoracic surgeons have received 696 National Institutes of Health grants totaling more than $1.5 billion in funding, with 48 surgeons actively serving as principal investigator of 66 R01 grants in 2020. The prevalence of research grants (7.4 vs 5.6 grants per 100 active surgeons, P < .0001), percentage of surgeons with a research grant (5.3% vs 4.7%, P = .0342), and number of research grants per funded surgeon (1.4 vs 1.2 grants, P < .0001) were significantly greater during the Scientific Affairs and Government Relations era (2003-2020) than the pre-Scientific Affairs and Government Relations era (1985-2002). The incidence of new research grants after surgeon participation in an American Association for Thoracic Surgery academic development program was significantly greater than that in the absence of participation (3.5 vs 1.1 new grants per 100 surgeons per year, P < .0001). CONCLUSIONS: Through dedicated efforts and programs, the American Association for Thoracic Surgery has provided effective support to help increase National Institutes of Health grant funding awarded to cardiothoracic surgeons.

Longitudinal analysis of National Institutes of Health funding for academic thoracic surgeons.

OBJECTIVE: National Institutes of Health (NIH) funding for academic (noncardiac) thoracic surgeons at the top-140 NIH-funded institutes in the United States was assessed. We hypothesized that thoracic surgeons have difficulty in obtaining NIH funding in a difficult funding climate. METHODS: The top-140 NIH-funded institutes' faculty pages were searched for noncardiac thoracic surgeons. Surgeon data, including gender, academic rank, and postfellowship training were recorded. These surgeons were then queried in NIH Research Portfolio Online Reporting Tools Expenditures and Results for their funding history. Analysis of the resulting grants (1980-2019) included grant type, funding amount, project start/end dates, publications, and a citation-based Grant Impact Metric to evaluate productivity. RESULTS: A total of 395 general thoracic surgeons were evaluated with 63 (16%) receiving NIH funding. These 63 surgeons received 136 grants totaling $228 million, resulting in 1772 publications, and generating more than 50,000 citations. Thoracic surgeons have obtained NIH funding at an increasing rate (1980-2019); however, they have a low percentage of R01 renewal (17.3%). NIH-funded thoracic surgeons were more likely to have a higher professorship level. Thoracic surgeons perform similarly to other physician-scientists in converting K-Awards into R01 funding. CONCLUSIONS: Contrary to our hypothesis, thoracic surgeons have received more NIH funding over time. Thoracic surgeons are able to fill the roles of modern surgeon-scientists by obtaining NIH funding during an era of increasing clinical demands. The NIH should continue to support this mission.

Deacetylation as a receptor-regulated direct activation switch for pannexin channels.

Activation of Pannexin 1 (PANX1) ion channels causes release of intercellular signaling molecules in a variety of (patho)physiological contexts. PANX1 can be activated by G protein-coupled receptors (GPCRs), including α1-adrenergic receptors (α1-ARs), but how receptor engagement leads to channel opening remains unclear. Here, we show that GPCR-mediated PANX1 activation can occur via channel deacetylation. We find that α1-AR-mediated activation of PANX1 channels requires Gαq but is independent of phospholipase C or intracellular calcium. Instead, α1-AR-mediated PANX1 activation involves RhoA, mammalian diaphanous (mDia)-related formin, and a cytosolic lysine deacetylase activated by mDia - histone deacetylase 6. HDAC6 associates with PANX1 and activates PANX1 channels, even in excised membrane patches, suggesting direct deacetylation of PANX1. Substitution of basally-acetylated intracellular lysine residues identified on PANX1 by mass spectrometry either prevents HDAC6-mediated activation (K140/409Q) or renders the channels constitutively active (K140R). These data define a non-canonical RhoA-mDia-HDAC6 signaling pathway for GαqPCR activation of PANX1 channels and uncover lysine acetylation-deacetylation as an ion channel silencing-activation mechanism.

Valve-sparing aortic root replacement after neonatal arterial switch operation.

Arterial switch operations (ASO) are lifesaving procedures performed on neonates to treat transposition of the great arteries. However, future operations on the neoaorta may be required due to dilation. We present a case of a 25-year-old female who presented with dilation of her neoaorta and required a David procedure. Her previous ASO resulted in an anterior lie of the pulmonary artery in front of the neoaorta, with both coronary arteries coming off anteriorly. We describe our approach to performing a David procedure on this patient with this unique anatomy.

ATP and large signaling metabolites flux through caspase-activated Pannexin 1 channels.

Pannexin 1 (Panx1) is a membrane channel implicated in numerous physiological and pathophysiological processes via its ability to support release of ATP and other cellular metabolites for local intercellular signaling. However, to date, there has been no direct demonstration of large molecule permeation via the Panx1 channel itself, and thus the permselectivity of Panx1 for different molecules remains unknown. To address this, we expressed, purified, and reconstituted Panx1 into proteoliposomes and demonstrated that channel activation by caspase cleavage yields a dye-permeable pore that favors flux of anionic, large-molecule permeants (up to ~1 kDa). Large cationic molecules can also permeate the channel, albeit at a much lower rate. We further show that Panx1 channels provide a molecular pathway for flux of ATP and other anionic (glutamate) and cationic signaling metabolites (spermidine). These results verify large molecule permeation directly through caspase-activated Panx1 channels that can support their many physiological roles.

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.

The Changing Face of Academic Surgery: Overrepresentation of Women among Surgeon-Scientists with R01 Funding.

BACKGROUND: There has been a recent focus on sex-based disparities within the field of academic surgery. However, the proportion of female surgeons conducting NIH-funded research is unknown. STUDY DESIGN: The NIH RePORTER (Research Portfolio Online Reporting Tools Expenditures and Results) was queried for R01 grants from surgery departments for which the principal investigator (PI) had a primary medical degree, as of October 2018. Characteristics of the PI and their respective grants were collected. Institutional faculty profiles were reviewed for PI and departmental characteristics. PIs were stratified by sex and compared using standard univariate statistics. RESULTS: There were a total of 212 R01 grants in surgery departments held by 159 PIs. Of these, 26.4% (n = 42) of R01-funded surgeons were female compared with the reported 19% of academic surgery female faculty (as reported by the Association of American Medical Colleges; p = 0.02). Women with R01 grants were more likely to be first-time grant recipients with no concurrent or previous NIH funding (21.4% vs 8.6%; p = 0.03) and less likely to have a previous R01 or equivalent grant (54.8% vs 73.5%; p = 0.03). Women were more likely to be from departments with a female surgery chair (31.0% vs 13.7%; p = 0.01) or a department with > 30% female surgeons (35.0% vs 18.2%; p = 0.03). CONCLUSIONS: Although female surgeons remain a minority in academic surgery, they hold a greater than anticipated proportion of NIH funding, with a high number of first-time grants, forming a crucial component of the next generation of surgeon-scientists.

Comprehensive National Institutes of Health funding analysis of academic cardiac surgeons.

OBJECTIVE: To determine trends in National Institutes of Health (NIH) funding for cardiac surgeons, hypothesizing they are at a disadvantage in obtaining funding owing to intensive clinical demands. METHODS: Cardiac surgeons (adult/congenital) currently at the top 141 NIH-funded institutions were identified using institutional websites. The NIH funding history for each cardiac surgeon was queried using the NIH Research Portfolio Online Reporting Tools Expenditures and Results (RePORTER). Total grant funding, publications, and type was collected. Academic rank, secondary degrees, and fellowship information was collected from faculty pages. Grant productivity was calculated using a validated grant impact metric. RESULTS: A total of 818 academic cardiac surgeons were identified, of whom 144 obtained 293 NIH grants totaling $458 million and resulting in 6694 publications. We identified strong associations between an institution's overall NIH funding rank and the number of cardiac surgeons, NIH grants to cardiac surgeons, and amount of NIH funding to cardiac surgeons (P < .0001 for all). The majority of NIH funding to cardiac surgeons is concentrated in the top quartile of institutions. Cardiac surgeons had a high conversion rates from K awards (mentored development awards) to R01s (6 of 14; 42.9%). Finally, we demonstrate that the rate of all NIH grants awarded to cardiac surgeons has increased, driven primarily by P and U (collaborative project) grants. CONCLUSIONS: NIH-funded cardiac surgical research has had a significant impact over the last 3 decades. Aspiring cardiac surgeon-scientists may be more successful at top quartile institutions owing to better infrastructure and mentorship.

Reduced-flow ex vivo lung perfusion to rehabilitate lungs donated after circulatory death.

BACKGROUND: Current ex vivo lung perfusion (EVLP) protocols aim to achieve perfusion flows of 40% of cardiac output or more. We hypothesized that a lower target flow rate during EVLP would improve graft function and decrease inflammation of donation after circulatory death (DCD) lungs. METHODS: A porcine DCD and EVLP model was utilized. Two groups (n = 4 per group) of DCD lungs were randomized to target EVLP flows of 40% (high-flow) or 20% (low-flow) predicted cardiac output based on 100 ml/min/kg. At the completion of 4 hours of normothermic EVLP using Steen solution, left lung transplantation was performed, and lungs were monitored during 4 hours of reperfusion. RESULTS: After transplant, left lung-specific pulmonary vein partial pressure of oxygen was significantly higher in the low-flow group at 3 and 4 hours of reperfusion (3-hour: 496.0 ± 87.7 mm Hg vs. 252.7 ± 166.0 mm Hg, p = 0.017; 4-hour: 429.7 ± 93.6 mm Hg vs. 231.5 ± 178 mm Hg, p = 0.048). Compliance was significantly improved at 1 hour of reperfusion (20.8 ± 9.4 ml/cm H2O vs. 10.2 ± 3.5 ml/cm H2O, p = 0.022) and throughout all subsequent time points in the low-flow group. After reperfusion, lung wet-to-dry weight ratio (7.1 ± 0.7 vs. 8.8 ± 1.1, p = 0.040) and interleukin-1ß expression (927 ± 300 pg/ng protein vs. 2,070 ± 874 pg/ng protein, p = 0.048) were significantly reduced in the low-flow group. CONCLUSIONS: EVLP of DCD lungs with low-flow targets of 20% predicted cardiac output improves lung function, reduces edema, and attenuates inflammation after transplant. Therefore, EVLP for lung rehabilitation should use reduced flow rates of 20% predicted cardiac output.

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.

Increasing circulating sphingosine-1-phosphate attenuates lung injury during ex vivo lung perfusion.

BACKGROUND: Sphingosine-1-phosphate regulates endothelial barrier integrity and promotes cell survival and proliferation. We hypothesized that upregulation of sphingosine-1-phosphate during ex vivo lung perfusion would attenuate acute lung injury and improve graft function. METHODS: C57BL/6 mice (n = 4-8/group) were euthanized, followed by 1 hour of warm ischemia and 1 hour of cold preservation in a model of donation after cardiac death. Subsequently, mice underwent 1 hour of ex vivo lung perfusion with 1 of 4 different perfusion solutions: Steen solution (Steen, control arm), Steen with added sphingosine-1-phosphate (Steen + sphingosine-1-phosphate), Steen plus a selective sphingosine kinase 2 inhibitor (Steen + sphingosine kinase inhibitor), or Steen plus both additives (Steen + sphingosine-1-phosphate + sphingosine kinase inhibitor). During ex vivo lung perfusion, lung compliance and pulmonary artery pressure were continuously measured. Pulmonary vascular permeability was assessed with injection of Evans Blue dye. RESULTS: The combination of 1 hour of warm ischemia, followed by 1 hour of cold ischemia created significant lung injury compared with lungs that were immediately harvested after circulatory death and put on ex vivo lung perfusion. Addition of sphingosine-1-phosphate or sphingosine kinase inhibitor alone did not significantly improve lung function during ex vivo lung perfusion compared with Steen without additives. However, group Steen + sphingosine-1-phosphate + sphingosine kinase inhibitor resulted in significantly increased compliance (110% ± 13.9% vs 57.7% ± 6.6%, P < .0001) and decreased pulmonary vascular permeability (33.1 ± 11.9 µg/g vs 75.8 ± 11.4 µg/g tissue, P = .04) compared with Steen alone. CONCLUSIONS: Targeted drug therapy with a combination of sphingosine-1-phosphate + sphingosine kinase inhibitor during ex vivo lung perfusion improves lung function in a murine donation after cardiac death model. Elevation of circulating sphingosine-1-phosphate via specific pharmacologic modalities during ex vivo lung perfusion may provide endothelial protection in marginal donor lungs leading to successful lung rehabilitation for transplantation.