Association of individual surgeon volume and postoperative outcome in esophagomyotomy for achalasia.

BACKGROUND: Many surgical disciplines have demonstrated superior outcomes when procedures are performed at "high-volume". Esophagomyotomy is commonly performed for achalasia, however it's unclear what constitutes "high-volume" for this procedure, and if individual procedure volume and outcome are related. We identified physicians performing esophagomyotomy, stratified them by individual case volume, and examined their outcomes with the hypothesis that high-volume surgeons will be associated with improved outcomes as compared to low-volume surgeons. METHODS: The 2015-2019 Florida Agency for Health Care Administration (AHCA) inpatient dataset was queried for esophagomyotomy. Surgeons who performed ≥ 10 procedures during the study period were placed into the high-volume cohort, and those performing < 10 into the low-volume cohort. Groups were compared by length of stay, discharge disposition, and postoperative complications. Patient demographics were evaluated using student's t test and chi square test, p < 0.05 considered significant. RESULTS: Six hundred and sixty-two procedures performed by 135 surgeons were identified. The mean number of esophagomyotomies per surgeon was 4.9 (Range 1-147). The high-volume group (n = 12) performed 362 of the 662 procedures (55%), while the low-volume group (n = 123) performed the remaining 300 (45%). Patients of high-volume physicians had decreased length of stay (1.4 ± 0.8 days vs 4.9 ± 6.7 days, p = 0.01) and were more likely to be discharged to home following surgery (92.8% vs 86.0, p = 0.04). High volume physicians also had statistically significant differences in rates of urinary tract infection (1.4% vs 4.0%, p = 0.034), postoperative malnutrition (5.8% vs 11.0%, p = 0.015), and postoperative fluid and electrolyte disorders (5.5% vs 13.3%, p < 0.0001). CONCLUSION: Surgeons who perform higher volumes of esophagomyotomies are associated with decreased length of stay, higher likelihood of patient discharge to home, and decreased rates of some postoperative complications. This research should prompt further inquiry into defining what constitutes a high-volume center in foregut surgery and their role in improving patient outcomes.

Contemporary utilization of the axillary artery in cardiac surgery.

INTRODUCTION: The axillary artery is a reliable inflow vessel when addressing pathology of the aortic root and aortic arch that may preclude standard central cannulation strategies. This narrative review examines the use of the axillary artery in cardiac surgery. Anatomy, indications for use, cannulation strategies, and potential complications will be discussed. METHODS: A comprehensive review of the current literature was performed using PubMed, Cochrane Review, and authoritative committee guidelines. A narrative review incorporating current available evidence was undertaken. COMMENT: Use of the axillary artery in select cardiac surgical cases is reliable, reproducible, and may be preferable in certain cases involving ascending aortic pathology, reoperative surgery, porcelain aorta, access for transcatheter valve therapies, and peripheral mechanical circulatory support.

A machine learning approach to high-risk cardiac surgery risk scoring.

INTRODUCTION: In patients undergoing high-risk cardiac surgery, the uncertainty of outcome may complicate the decision process to intervene. To augment decision-making, a machine learning approach was used to determine weighted personalized factors contributing to mortality. METHODS: American College of Surgeons National Surgical Quality Improvement Program was queried for cardiac surgery patients with predicted mortality ≥10% between 2012 and 2019. Multiple machine learning models were investigated, with significant predictors ultimately used in gradient boosting machine (GBM) modeling. GBM-trained data were then used for local interpretable model-agnostic explanations (LIME) modeling to provide individual patient-specific mortality prediction. RESULTS: A total of 194 patient deaths among 1291 high-risk cardiac surgeries were included. GBM performance was superior to other model approaches. The top five factors contributing to mortality in LIME modeling were preoperative dialysis, emergent cases, Hispanic ethnicity, steroid use, and ventilator dependence. LIME results individualized patient factors with model probability and explanation of fit. CONCLUSIONS: The application of machine learning techniques provides individualized predicted mortality and identifies contributing factors in high-risk cardiac surgery. Employment of this modeling to the Society of Thoracic Surgeons database may provide individualized risk factors contributing to mortality.

Regulation of the thrombin/protease-activated receptor 1 axis by chemokine (CXC motif) receptor 4.

The chemokine receptor CXCR4, a G protein-coupled receptor (GPCR) capable of heteromerizing with other GPCRs, is involved in many processes, including immune responses, hematopoiesis, and organogenesis. Evidence suggests that CXCR4 activation reduces thrombin/protease-activated receptor 1 (PAR1)-induced impairment of endothelial barrier function. However, the mechanisms underlying cross-talk between CXCR4 and PAR1 are not well-understood. Using intermolecular bioluminescence resonance energy transfer and proximity ligation assays, we found that CXCR4 heteromerizes with PAR1 in the HEK293T expression system and in human primary pulmonary endothelial cells (hPPECs). A peptide analog of transmembrane domain 2 (TM2) of CXCR4 interfered with PAR1:CXCR4 heteromerization. In HTLA cells, the presence of CXCR4 reduced the efficacy of thrombin to induce ß-arrestin-2 recruitment to recombinant PAR1 and enhanced thrombin-induced Ca2+ mobilization. Whereas thrombin-induced extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation occurred more transiently in the presence of CXCR4, peak ERK1/2 phosphorylation was increased when compared with HTLA cells expressing PAR1 alone. CXCR4-associated effects on thrombin-induced ß-arrestin-2 recruitment to and signaling of PAR1 could be reversed by TM2. In hPPECs, TM2 inhibited thrombin-induced ERK1/2 phosphorylation and activation of Ras homolog gene family member A. CXCR4 siRNA knockdown inhibited thrombin-induced ERK1/2 phosphorylation. Whereas thrombin stimulation reduced surface expression of PAR1, CXCR4, and PAR1:CXCR4 heteromers, chemokine (CXC motif) ligand 12 stimulation reduced surface expression of CXCR4 and PAR1:CXCR4 heteromers, but not of PAR1. Finally, TM2 dose-dependently inhibited thrombin-induced impairment of hPPEC monolayer permeability. Our findings suggest that CXCR4:PAR1 heteromerization enhances thrombin-induced G protein signaling of PAR1 and PAR1-mediated endothelial barrier disruption.

Characterization of heteromeric complexes between chemokine (C-X-C motif) receptor 4 and α1-adrenergic receptors utilizing intermolecular bioluminescence resonance energy transfer assays.

Recently, we reported that chemokine (C-X-C motif) receptor 4 (CXCR4) heteromerizes with α1-adrenergic receptors (AR) on the cell surface of vascular smooth muscle cells, through which the receptors cross-talk. Direct biophysical evidence for CXCR4:α1-AR heteromers, however, is lacking. Here we utilized bimolecular luminescence/fluorescence complementation (BiLC/BiFC) combined with intermolecular bioluminescence resonance energy transfer (BRET) assays in HEK293T cells to evaluate CXCR4:α1a/b/d-AR heteromerization. Atypical chemokine receptor 3 (ACKR3) and metabotropic glutamate receptor 1 (mGlu1R) were utilized as controls. BRET between CXCR4-RLuc (Renilla reniformis) and enhanced yellow fluorescent protein (EYFP)-tagged ACKR3 or α1a/b/d-ARs fulfilled criteria for constitutive heteromerization. BRET between CXCR4-RLuc and EYFP or mGlu1R-EYFP were nonspecific. BRET50 for CXCR4:ACKR3 and CXCR4:α1a/b/d-AR heteromers were comparable. Stimulation of cells with phenylephrine increased BRETmax of CXCR4:α1a/b/d-AR heteromers without affecting BRET50; stimulation with CXCL12 reduced BRETmax of CXCR4:α1a-AR heteromers, but did not affect BRET50 or BRETmax/50 for CXCR4:α1b/d-AR. A peptide analogue of transmembrane domain (TM) 2 of CXCR4 reduced BRETmax of CXCR4:α1a/b/d-AR heteromers and increased BRET50 of CXCR4:α1a/b-AR interactions. A TM4 analogue of CXCR4 did not alter BRET. We observed CXCR4, α1a-AR and mGlu1R homodimerization by BiFC/BiLC, and heteromerization of homodimeric CXCR4 with proto- and homodimeric α1a-AR by BiFC/BiLC BRET. BiFC/BiLC BRET for interactions between homodimeric CXCR4 and homodimeric mGlu1R was nonspecific. Our findings suggest that the heteromerization affinity of CXCR4 for ACKR3 and α1-ARs is comparable, provide evidence for conformational changes of the receptor complexes upon agonist binding and support the concept that proto- and oligomeric CXCR4 and α1-ARs constitutively form higher-order hetero-oligomeric receptor clusters.

Postoperative Capnocytophaga Sputigena Presenting as Diffuse Recalcitrant Intra-abdominal Abscesses.

Capnocytophaga sputigena is rarely implicated as the cause of postsurgical intra-abdominal abscess because it is almost exclusively found in oral flora. Despite its rarity in intra-abdominal infection, there are examples of this atypical presentation, and an awareness of this organism as a potential etiology of surgical infection is relevant for both obstetric and general surgeons. We report a case of a young female who presented just over a week after an uncomplicated C-section with complaint of abdominal discomfort and fevers. Imaging revealed multiple intra-abdominal fluid collections and cultures revealed the presence of C. sputigena. Percutaneous drainage and intravenous antibiotics were unable to provide significant source control, so she underwent surgical exploration with a multi-specialty team of obstetric and acute care surgeons. Although postsurgical pelvic abscesses are rarely due to C. sputigena, this organism has been documented to serve as a source of intra-abdominal infection.

Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock.

Systemic concentrations of chemokine CCL2, an agonist at chemokine receptors CCR2/3/5, have been associated with hemodynamic instability after traumatic-hemorrhagic shock. We reported previously that the CCR2 antagonist INCB3284 prevents cardiovascular collapse and reduces fluid requirements after 30min of hemorrhagic shock (HS), whereas the CCR5 antagonist Maraviroc was ineffective. The effects of CCR3 blockade after HS are unknown and information on the therapeutic potential of INCB3284 after longer periods of HS and in HS models in the absence of fluid resuscitation (FR) is lacking. The aims of the present study were to assess the effects of CCR3 blockade with SB328437 and to further define the therapeutic efficacy of INCB3284. In series 1-3, Sprague-Dawley rats were hemorrhaged to a mean arterial blood pressure (MAP) of 30mmHg, followed by FR to MAP of 60mmHg or systolic blood pressure of 90mmHg. Series 1: 30min HS and FR until t = 90min. SB328437 at t = 30min dose-dependently reduced fluid requirements by >60%. Series 2: 60min HS and FR until t = 300min. INCB3284 and SB328437 at t = 60min reduced fluid requirements by more than 65% (p<0.05 vs. vehicle) and 25% (p>0.05 vs. vehicle), respectively, until t = 220min. Thereafter, all animals developed a steep increase in fluid requirements. Median survival time was 290min with SB328437 and >300min after vehicle and INCB3284 treatment (p<0.05). Series 3: HS/FR as in series 2. INCB3284 at t = 60min and t = 200min reduced fluid requirements by 75% until t = 300min (p<0.05 vs. vehicle). Mortality was 70% with vehicle and zero with INCB3284 treatment (p<0.05). Series 4: INCB3284 and SB328437 did not affect survival time in a lethal HS model without FR. Our findings further support the assumption that blockade of the major CCL2 receptor CCR2 is a promising approach to improve FR after HS and document that the dosing of INCB3284 can be optimized.

The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock.

Clinical correlations suggest that systemic chemokine (C-C motif) ligand (CCL) 2 release may contribute to blood pressure regulation and the development of hemodynamic instability during the early inflammatory response to traumatic-hemorrhagic shock. Thus, we investigated whether blockade of the principal CCL2 receptor chemokine (C-C motif) receptor (CCR) 2 affects blood pressure in normal animals, and hemodynamics and resuscitation fluid requirements in hemorrhagic shock models. DESIGN: Randomized prospective treatment study. SETTING: University laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: First, treatment of healthy anesthetized rats with increasing doses of INCB3284 or vehicle. Second, rats were hemorrhaged for 30 minutes, followed by treatment with the CCR2 antagonist INCB3284 (1.1 and 5.5 µmol/kg), the CCR5 antagonist Maraviroc (=control, 5.5 µmol/kg) or vehicle, and subsequent fluid resuscitation to maintain blood pressure until t = 90 minutes. Third, treatment of rats with 5 µmol/kg INCB3284 or vehicle after hemorrhage and fluid resuscitation until t = 300 minutes. MEASUREMENTS AND MAIN RESULTS: INCB3284 did not affect intrinsic function of isolated rat resistance arteries in pressure myography experiments. Blood pressure in anesthetized vehicle-treated animals continuously decreased by 0.09 ± 0.01 mm Hg/min (p < 0.001) but remained constant after INCB3284 injections. Systemic concentrations of the CCR2 agonists CCL2, CCL5, and CCL11 increased during hemorrhage and fluid resuscitation. INCB3284 dose-dependently reduced fluid requirements by 58% ± 11% in short-term experiments, whereas Maraviroc and vehicle-treated animals were indistinguishable. When resuscitation was performed until t = 300 minutes, INCB3284 reduced fluid requirements by 62% ± 6%, prevented from hemodynamic decompensation, reduced mortality from 50% with vehicle treatment to zero, and reduced overall tissue wet-weight/dry-weight ratios. CONCLUSIONS: Our findings suggest that CCR2 is involved in the regulation of normal cardiovascular function and during the cardiovascular stress response to hemorrhagic shock and fluid resuscitation. The present study identifies CCR2 as a drug target to reduce fluid requirements and to prevent death from hemodynamic decompensation during resuscitation from hemorrhagic shock.

Outcomes of Transcatheter and Surgical Aortic Valve Replacement in Distressed Socioeconomic Communities.

Objective Patients of low socioeconomic status have an increased risk of complications following cardiac surgery. We aimed to identify disparities in patients undergoing aortic valve replacement using the Distressed Communities Index (DCI), a comparative measure of community well-being. The DCI incorporates seven distinct socioeconomic indicators into a single composite score to depict the economic well-being of a community. Methods The Healthcare Cost and Utilization Project State Inpatient Database (HCUP-SID) for Florida and Washington was queried to identify patients undergoing surgical and transcatheter aortic valve replacement (surgical aortic valve replacement [SAVR], transcatheter aortic valve replacement [TAVR]) between 2012-2015. Patients undergoing TAVR and SAVR were propensity-matched and stratified based on the quintile of DCI score. A distressed community was defined as those in quintiles 4 and 5 (at-risk and distressed, respectively); a non-distressed community was defined as those in quintiles 1 and 2 (prosperous and comfortable, respectively). Outcomes following aortic valve replacement were compared across groups in distressed communities. Propensity score matching was used to balance baseline covariates between groups. Results A total of 27,591 patients underwent aortic valve replacement. After propensity matching, 5,331 patients were identified in each TAVR and SAVR group. Distressed TAVR patients had lower rates of postoperative pneumonia (7.6% vs. 3.8%, p<0.001), sepsis (3.6% vs. 1.9%, p<0.05), and cardiac complications (15.4% vs. 7.5%, p<0.001) when compared to highly distressed SAVR patients. When comparing distressed SAVR and TAVR and low distressed SAVR and TAVR groups, no significant difference was found in postoperative outcomes, except distressed TAVR experienced more cases of UTI. Conclusions Highly distressed TAVR patients had lower incidences of postoperative sepsis, pneumonia, and cardiac complications when compared to the highly distressed SAVR cohort. Patients undergoing TAVR in highly distressed communities had an increased incidence of postoperative urinary tract infection. DCI may be a useful adjunct to current risk scoring systems.

Machine Learning Refinement of the NSQIP Risk Calculator: Who Survives the "Hail Mary" Case?

BACKGROUND: The American College of Surgeons (ACS) NSQIP risk calculator helps guide operative decision making. In patients with significant surgical risk, it may be unclear whether to proceed with "Hail Mary"-type interventions. To refine predictions, a local interpretable model-agnostic explanations machine (LIME) learning algorithm was explored to determine weighted patient-specific factors' contribution to mortality. STUDY DESIGN: The ACS-NSQIP database was queried for all surgical patients with mortality probability greater than 50% between 2012 and 2019. Preoperative factors (n = 38) were evaluated using stepwise logistic regression; 26 significant factors were used in gradient boosted machine (GBM) modeling. Data were divided into training and testing sets, and model performance was substantiated with 10-fold cross validation. LIME provided individual subject mortality. The GBM-trained model was interpolated to LIME, and predictions were made using the test dataset. RESULTS: There were 6,483 deaths (53%) among 12,248 admissions. GBM modeling displayed good performance (area under the curve = 0.65, 95% CI 0.636-0.671). The top 5 factors (% contribution) to mortality included: septic shock (27%), elevated International Normalized Ratio (22%), ventilator-dependence (14%), thrombocytopenia (14%), and elevated serum creatinine (5%). LIME modeling subset personalized patients by factors and weights on survival. In the entire cohort, mortality positive predictive value with 2 factor combinations was 53.5% (specificity 0.713), 3 combinations 64.2% (specificity 0.835), 4 combinations 72.1% (specificity 0.943), and all 5 combinations 77.9% (specificity 0.993). Conversely, mortality positive predictive value fell to 34% in the absence of 4 factors. CONCLUSIONS: Through the application of machine learning algorithms (GBM and LIME), our model individualized predicted mortality and contributing factors with substantial ACS-NSQIP predicted mortality. USE of machine learning techniques may better inform operative decisions and family conversations in cases of significant surgical risk.

Predictive modeling of in-hospital mortality following elective surgery.

INTRODUCTION: The specific healthcare macroenvironment factors contributing to in-hospital mortality following elective surgery remain nuanced. We hypothesize an accurate global elective surgical mortality model can be created. METHODS: FL AHCA and Hospital Compare (2016-2019) were queried for in-hospital mortality following elective surgeries. Stepwise logistic regression with 47 patient and hospital factors was followed by gradient boosting machine (GBM) modeling describing the relative influence on risk for in-hospital mortality. Deceased and surviving patients were matched (1:2) to perform univariate analysis and logistic regression of significant factors. RESULTS: A total of 511,897 admissions, 2,266 patient deaths and 162 Florida hospitals were included. GBM factors (AUC 0.94) included post-operative patient and hospital factors. In the final regression model, patient age older than 70 years of age and hospital 5-star rating were significant (OR 2.87, 0.47, respectively). Hospitals rated 5-stars were protective of mortality. CONCLUSION: In-patient mortality following elective surgery is influenced by patient and hospital level factors. Efforts should be made to mitigate these risks or enhance those that are protective.

Heteromerization between α1B -adrenoceptor and chemokine (C-C motif) receptor 2 biases α1B -adrenoceptor signaling: Implications for vascular function.

Previously, we reported that chemokine (C-C motif) receptor 2 (CCR2) heteromerizes with α1B -adrenoceptor (α1B -AR) in leukocytes, through which α1B -AR controls CCR2. Whether such heteromers are expressed in human vascular smooth muscle cells (hVSMCs) is unknown. Bioluminescence resonance energy transfer confirmed formation of recombinant CCR2:α1b -AR heteromers. Proximity ligation assays detected CCR2:α1B -AR heteromers in hVSMCs and human mesenteric arteries. CCR2:α1B -AR heteromerization per se enhanced α1B -AR-mediated Gαq -coupling. Chemokine (C-C motif) ligand 2 (CCL2) binding to CCR2 inhibited Gαq activation via α1B -AR, cross-recruited ß-arrestin to and induced internalization of α1B -AR in recombinant systems and in hVSMCs. Our findings suggest that CCR2 within CCR2:α1B -AR heteromers biases α1B -AR signaling and provide a mechanism for previous observations suggesting a role for CCL2/CCR2 in the regulation of cardiovascular function.

Chemokine receptor antagonists with α1-adrenergic receptor blocker activity.

OBJECTIVES: Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C-C motif) receptor 2 (CCR2) antagonist RS504393 is known to compete with ligand binding to α1-adrenoceptors, we tested a panel of 10 CCR antagonists for interactions with α1-adrenoceptors to evaluate potential cardiovascular activities and side-effect profiles. METHODS: The PRESTO-Tango ß-arrestin recruitment assay was utilized to test whether the CCR antagonists interfere with α1b-AR activation upon stimulation with phenylephrine. Pressure myography with isolated rat resistance arteries was employed to assess their effects on phenylephrine-induced vasoconstriction. The following antagonists were tested: CCR1-BX471, BX513, BI639667; CCR2-RS504393, INCB3284; CCR3-SB328437; and CCR4-AZD2098, and C021; CCR5-Maraviroc; CCR10-BI6901. The pan-α1-adrenoceptor antagonist prazosin was used as control. RESULTS: Among the CCR antagonists tested, RS504393, BX513, and C021 inhibited phenylephrine-induced ß-arrestin recruitment to α1b-adrenoceptor and phenylephrine-induced vasoconstriction. While RS504393 functioned as a competitive α1-adrenoceptor blocker, BX513 and C021 functioned as noncompetitive α1-adrenoceptor antagonists in both assay systems. Furthermore, RS504393, BX513, and C021 dose-dependently dilated arteries that were fully preconstricted with phenylephrine. CONCLUSIONS: Our data suggest that CCR antagonists should be screened for cross-reactivity with α1-adrenoceptors to exclude potential adverse cardiovascular effects when used as anti inflammatory drugs.

Oligometastatic Adenocarcinoma of the Esophagus: Current Understanding, Diagnosis, and Therapeutic Strategies.

Esophageal adenocarcinoma is an aggressive cancer of increasing incidence and is associated with poor prognosis. The early recognition of synchronous and metachronous oligometastasis in esophageal adenocarcinoma may allow for prompt intervention and potentially improved survival. However, curative approaches to oligometastatic esophageal disease remain unproven and may represent an area of emerging divergence of opinion for surgical and medical oncologists. We sought to identify the current understanding and evidence for management of oligometastatic esophageal adenocarcinoma by performing a thorough review of the available literature.

Class A G protein-coupled receptors assemble into functional higher-order hetero-oligomers.

Although class A seven-transmembrane helix (7TM) receptor hetero-oligomers have been proposed, information on the assembly and function of such higher-order hetero-oligomers is not available. Utilizing bioluminescence resonance energy transfer (BRET), bimolecular luminescence/fluorescence complementation (BiLC/BiFC), and BiLC/BiFC BRET in HEK293T cells, we provide evidence that chemokine (C-X-C motif) receptor 4, atypical chemokine receptor 3, α1a -adrenoceptor, and arginine vasopressin receptor 1A form hetero-oligomers composed of 2-4 different protomers. We show that hetero-oligomerization per se and ligand binding to individual protomers regulate agonist-induced coupling to the signaling transducers of interacting receptor partners. Our findings support the concept that receptor hetero-oligomers form supramolecular machineries with molecular signaling properties distinct from the individual protomers. These findings provide a mechanism for the phenomenon of context-dependent receptor function.

The future surgical training paradigm: Virtual reality and machine learning in surgical education.

Surgical training has undergone substantial change in the last few decades. As technology and patient complexity continues to increase, demands for novel approaches to ensure competency have arisen. Virtual reality systems augmented with machine learning represents one such approach. The ability to offer on-demand training, integrate checklists, and provide personalized, surgeon-specific feedback is paving the way to a new era of surgical training. Machine learning algorithms that improve over time as they acquire more data will continue to refine the education they provide. Further, fully immersive simulated environments coupled with machine learning analytics provide real-world training opportunities in a safe atmosphere away from the potential to harm patients. Careful implementation of these technologies has the potential to increase access and improve quality of surgical training and patient care and are poised to change the landscape of current surgical training. Herein, we describe the current state of virtual reality coupled with machine learning for surgical training, future directions, and existing limitations of this technology.

WITHDRAWN: Invited commentary on "Registry-based trainee assessments: Leveraging a quality collaborative for surgical education".

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Natural and engineered chemokine (C-X-C motif) receptor 4 agonists prevent acute respiratory distress syndrome after lung ischemia-reperfusion injury and hemorrhage.

We compared therapeutic properties of natural and engineered chemokine (C-X-C motif) receptor 4 (CXCR4) agonists in a rat acute respiratory distress syndrome (ARDS) model utilizing the PaO2/FiO2-ratio as a clinically relevant primary outcome criterion. Ventilated rats underwent unilateral lung ischemia from t = 0-70 min plus hemorrhage to a mean arterial blood pressure (MAP) of 30 mmHg from t = 40-70 min, followed by reperfusion/fluid resuscitation until t = 300 min. Natural CXCR4 agonists (CXCL12, ubiquitin) and engineered CXCL12 variants (CXCL121, CXCL22, CXCL12K27A/R41A/R47A, CXCL12 (3-68)) were administered within 5 min of fluid resuscitation. Animals treated with vehicle or CXCL12 (3-68) reached criteria for mild and moderate ARDS between t = 90-120 min and t = 120-180 min, respectively, and remained in moderate ARDS until t = 300 min. Ubiquitin, CXCL12, CXCL121 and CXCL122 prevented ARDS development. Potencies of CXCL12/CXCL121/CXCL122 were higher than the potency of ubiquitin. CXCL12K27A/R41A/R47A was inefficacious. CXCL121 > CXCL12 stabilized MAP and reduced fluid requirements. CXCR4 agonists at doses that preserved lung function reduced histological injury of the post-ischemic lung and reduced mortality from 55 to 9%. Our findings suggest that CXCR4 protein agonists prevent development of ARDS and reduce mortality in a rat model, and that development of new engineered protein therapeutics with improved pharmacological properties for ARDS is possible.