BACKGROUND Prolonged lung preservation by ex vivo lung perfusion (EVLP) is an important objective in lung transplantation. Maintaining stable perfusate composition is key, and integrated dialysis is a potential method. We examined the suitability of integrated hemodialysis with EVLP to maintain perfusate homeostasis and extend perfusion time. METHODS Lungs were procured from 30-40 kg Yorkshire pigs. The clinical-grade TransMedics OCSTM Lung system was used with perfusate consisting of autologous washed RBCs and TransMedics OCSTM solution. Hemodialysis was added to the venous return line of the device and begun 1-hour after the start of perfusion. Physiological parameters and blood gas data were monitored during perfusion, and perfusate cytokine levels evaluated at prespecified times. RESULTS Hemodialysis moderately stabilized electrolyte levels and reduced lactate, but promoted the more rapid development of edema, resulting in shorter mean preservation time (control (n=8) vs hemodialysis (n=6): 24 hours vs 7.5 hours, p=0.034). Employing a high sodium (HiNa) dialysate (n=5) reduced edema formation, but did not significantly extend lung preservation. Notably, significant upregulation of interferon gamma (p<0.001) and IL-8 (p=0.005) was observed in this group, as well as upregulation of the anti-inflammatory cytokine IL-10 (p=0.0037). CONCLUSIONS Integrating hemodialysis into an EVLP circuit was detrimental to graft preservation, leading to progressive edema and reduced graft survival. Despite stabilizing circulating electrolyte concentrations, adding dialysis resulted in pro-inflammatory cytokine upregulation, further reflecting declining graft viability. These findings demonstrate the standard hemodialysis protocol is inadequate for perfusate reconditioning during long-term EVLP, requiring modification for this application.

Ex-vivo lung perfusion (EVLP) has emerged as a transformative technique in lung transplantation, offering a solution for evaluating and rehabilitating donor lungs that would otherwise be deemed unsuitable. This review article examines the significant advancements in EVLP technology and its application in clinical practice. We discuss the criteria for selection and rehabilitation of donor lungs, emphasizing the use of EVLP for lungs with compromised function due to factors like prolonged ischemic time and donor smoking history. Further, we elaborate on the technological advancements that have improved the functional assessment of lungs, including the development of more sophisticated perfusion solutions and the integration of artificial intelligence for real-time assessment. Additionally, we discuss the future prospects of EVLP, focusing on potential innovations in perfusion solutions, the integration of regenerative medicine and gene therapy to improve allograft quality. Through this comprehensive review, we aim to provide a clear understanding of the current status of EVLP and its promising future directions, ultimately contributing to improved outcomes in lung transplantation.

Acute cellular rejection is a key contributor to chronic lung allograft dysfunction following transplantation; while treatable, traditional immunosuppressive therapies are associated with significant side effects. Gene therapy offers an approach to modulate recipient immune responses while minimizing the toxicity of conventional immunosuppressive therapy. In this study, we evaluated adenoassociated virus (AAV)-mediated programmed death-ligand (PD-L)1 overexpression, an inhibitory ligand of T cells, in a rat single-lung transplant model. Allogeneic Brown Norway lungs were transplanted into Fischer F344 recipients and assigned to 3 groups: (1) AAV9-PD-L1 via the bronchus during static cold storage, (2) no-virus control, or (3) AAV9-luciferase control. All animals received cytotoxic T lymphocyte-associated protein 4 immunoglobulin on postoperative day (POD)1, and killed on POD14. Rejection was evaluated by a blinded lung transplant pathologist, and PD-L1 expression and CD8+ T cell infiltration assessed via immunohistochemistry. By POD14, the AAV9-PD-L1 group displayed significantly reduced rejection severity (mean score 1.40) compared to controls (mean 3.60; p=0.005). The AAV9-luciferase group exhibited comparable rejection scores to no-virus controls (mean 3.5). Immunohistochemistry confirmed exogenous PD-L1 expression, however no significant difference in CD8+ T cell count was observed between groups. These findings demonstrate that AAV-PD-L1 gene delivery can attenuate acute cellular rejection in lung transplants, offering a potential strategy to improve outcomes.

Short-statured lung transplant candidates experience longer waitlist times than taller ones. The new composite allocation score (CAS) includes height to enhance allocation equity. We assessed the impact of CAS on waitlist outcomes for different height groups. We queried a national transplant database for lung transplant candidates listed from 2021 to 2024, categorized into 4 height groups: ≤162 cm, 162 to 170 cm, 170 to 176.5 cm, and >176.5 cm. Competing risk and Cox regression models assessed the impact of height on waitlist outcomes, including an interaction term between height and allocation era to assess effect modification. Of the 9383 candidates identified, those >176.5 cm had an increased likelihood of transplantation (subdistribution hazard ratio [sHR]: 1.15) compared to the 170 to 176.5 cm group, while those ≤162 cm had a lower likelihood (sHR: 0.70). The overall likelihood of transplantation was higher in the CAS era (sHR: 1.17). The interaction term for height ≤162 cm and CAS era was significant (sHR: 1.15), suggesting a modest improvement in access for this group under CAS. Further, candidates ≤162 cm experienced a higher hazard of mortality in the CAS era (HR: 1.60). These findings suggest that CAS modestly improves access for the shortest candidates, but refinements are needed to address ongoing inequities in this population.

Background:Current clinical ex vivo lung perfusion (EVLP) perfuses the pulmonary arteries (PA) but not the bronchial arteries (BA) that normally supply the upper airway. We hypothesized that the PA alone do not fully perfuse this region during EVLP, which could lead to hypoxic injury in the central airways, especially with extended preservation. In this study, we demonstrate a method for dual-route EVLP (D-EVLP) that perfuses both the PA and BA to improve lung preservation. Methods:Lungs were procured from 30- to 40-kg female pigs and perfused for up to 3 hours. Standard single-route control EVLP (C-EVLP) was compared to a D-EVLP approach consisting of PA inflow along with oxygenated BA inflow via cannulation through a segment of the thoracic aorta to achieve bronchoesophageal artery circulation. Results:Airway perfusion by BA flow was confirmed by injecting methylene blue. The mean total perfusion flows of D-EVLP and C-EVLP were 915 ± 60.2 mL/minute and 645 ± 46.5 mL/minute at 3 hours, respectively. Lower vascular resistance also was observed with D-EVLP (mean, 878 ± 109 dynes∗second/cm5 vs 1689 ± 194 dynes∗second/cm5). The PaO2/fraction of inspired oxygen ratio (mean, 589 ± 28 for D-EVLP, 587 ± 20 for C-EVLP) and dynamic compliance (30.8 ± 3.0 mL/cmH2O for D-EVLP, 30.3 ± 6.3 mL/cmH2O for C-EVLP) were comparable after 3 hours of preservation. In central and distal airways, hypoxia-inducible factor 1α, a marker of hypoxia measured by immunohistochemistry, was lower in D-EVLP compared to C-EVLP. Conclusions:The present study demonstrates the D-EVLP is feasible in a large-animal model and provides evidence that it may reduce airway ischemia compared to standard EVLP. Further investigation is warranted to determine the extent to which D-EVLP elicits superior graft preservation during extended perfusion and, ultimately, post-transplantation outcomes.

Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.

BACKGROUND:Ischemia-reperfusion injury (IRI) stands as a major trigger for primary graft dysfunction (PGD) in lung transplantation (LTx). Especially in LTx from donation after cardiac death (DCD), effective control of IRI following warm ischemia (WIRI) is crucial to prevent PGD. This study aimed to identify the key factors affecting WIRI in LTx from DCD. METHODS:Previously reported RNA-sequencing dataset of lung WIRI was reanalyzed to identify nuclear receptor subfamily 4 group A member 1 (NR4A1) as the immediate early gene for WIRI. Dynamics of NR4A1 expression were verified using a mouse hilar clamp model. To investigate the role of NR4A1 in WIRI, a mouse model of LTx from DCD was established using Nr4a1 knockout (Nr4a1-/-) mice. RESULTS:NR4A1 was located around vascular cells, and its protein levels in the lungs increased rapidly and transiently during WIRI. LTｘ from Nr4a1-/- donors significantly improved pulmonary graft function compared to wild-type donors. Histological analysis showed decreased microvascular endothelial cell death, neutrophil infiltration, and albumin leakage. Evans blue permeability assay demonstrated maintained pulmonary microvascular barrier integrity in grafts from Nr4a1-/- donors, correlating with diminished pulmonary edema. However, NR4A1 did not significantly affect the inflammatory response during WIRI, and IRI was not suppressed when a wild-type donor lung was transplanted into the Nr4a1-/- recipient. CONCLUSIONS:Donor NR4A1 plays a specialized role in the positive regulation of endothelial cell injury and microvascular hyperpermeability. These findings demonstrate the potential of targeting NR4A1 interventions to alleviate PGD and improve outcomes in LTx from DCD.

Background. Ex vivo kidney perfusion is an evolving platform that demonstrates promise in preserving and rehabilitating the kidney grafts. Despite this, there is little consensus on the optimal perfusion conditions. Hypothermic perfusion offers limited functional assessment, whereas normothermic perfusion requires a more complex mechanical system and perfusate. Subnormothermic machine perfusion (SNMP) has the potential to combine the advantages of both approaches but has undergone limited investigation. Therefore, the present study sought to determine the suitability of SNMP for extended kidney preservation. Methods. SNMP at 22–25 °C was performed on a portable device for 24 h with porcine kidneys. Graft assessment included measurement of mechanical parameters and biochemical analysis of the perfusate using point-of-care tests. To investigate the viability of kidneys preserved by SNMP, porcine kidney autotransplants were performed in a donation after circulatory death (DCD) model. SNMP was also compared with static cold storage (SCS). Finally, follow-up experiments were conducted in a subset of human kidneys to test the translational significance of findings in porcine kidneys. Results. In the perfusion-only cohort, porcine kidneys all displayed successful perfusion for 24 h by SNMP, evidenced by stable mechanical parameters and biological markers of graft function. Furthermore, in the transplant cohort, DCD grafts with 30 min of warm ischemic injury demonstrated superior posttransplant graft function when preserved by SNMP in comparison with SCS. Finally, human kidneys that underwent 24-h perfusion exhibited stable functional and biological parameters consistent with observations in porcine organs. Conclusions. These observations demonstrate the suitability and cross-species generalizability of subnormothermic machine perfusion to maintain stable kidney perfusion and provide foundational evidence for improved posttransplant graft function of DCD kidneys after SNMP compared with SCS.

Background. The clinical success of liver transplantation has led to increased demand, requiring further expansion of the donor pool. Therapeutic interventions to optimize organs from donation after circulatory death (DCD) have significant potential to mitigate the organ shortage. Dysfunction in DCD liver grafts is mediated by microvascular thrombosis during the warm ischemic period, and strategies that reduce this thrombotic burden may improve graft function. We hypothesized that the administration of the fibrinolytic enzyme plasmin to the donor organ during the cold storage period would reduce the thrombotic burden and improve DCD liver graft function. Methods. In 2 separate cohorts, 32 syngeneic orthotopic rat liver transplants were performed in Lewis rats. Livers were procured from donors with 45 min of warm ischemic injury. Liver grafts were flushed with histidine-tryptophan-ketoglutarate preservation solution mixed with either plasmin (experimental group) or albumin (control group). All investigators were blinded to treatment group. After preparing the liver for implant using a modified cuff technique, the liver was stored for 1 h by static cold storage at 4 °C. Immediately before implantation, the liver graft was flushed, and this effluent was analyzed for fibrin degradation products to determine graft clot burden. Twenty-four hours following transplantation, animals were euthanized, and samples were collected. Results. Recipient survival was significantly higher for DCD liver grafts treated with plasmin compared with control. Moreover, histology of liver graft tissue immediately before implant reflected significantly reduced congestion in plasmin-treated livers (score, mean ± SD: 0.73 ± 0.59 versus 1.12 ± 0.48; P = 0.0456). The concentration of fibrin degradation products in the final flush before implantation was significantly reduced in plasmin-treated livers (743 ± 136 versus 10 919 ± 4642 pg/mL; P = 0.0001), reflecting decreased clot burden in the graft. Conclusions. The present study demonstrates that plasmin improves survival and may reduce thrombotic burden in DCD liver grafts with prolonged warm ischemic injury, meriting further study.

PurposeBronchopleural fistula (BPF) is a serious complication of lung resection. To avoid BPF, the bronchial stump/anastomotic site is often covered with a flap of surrounding tissue. One risk factor for BPF is radical lung resection after induction chemoradiotherapy for lung cancer. We retrospectively reviewed our database to elucidate the characteristics of tissue flaps that prevent BPF.MethodsThis retrospective study included 152 patients treated between 1999 and 2019. We examined the clinicopathological characteristics, including the type and thickness of the tissue flap used to cover the bronchial stump/anastomotic site, and postoperative complications, including BPF.ResultsBPF occurred in 5 patients (3.3%). All 5 patients had complications that could have affected delayed wound healing, such as pneumonia. The covering tissue flap thickness was significantly greater in patients without BPF than in those who developed BPF (p = 0.0290). Additionally, the tissue flap thickness was significantly greater than in those with BPF (p = 0.0077), even in high-risk patients who developed pneumonia or radiation pneumonitis on the operative side within 6 months postoperatively.ConclusionPerioperative management is crucial to avoid complications affecting the healing of the bronchial stump/anastomotic site, and the covering tissue flap thickness may be an important factor in avoiding or minimizing BPF.

Donation after circulatory death (DCD) heart procurement is done using either direct procurement (DP) or thoracoabdominal normothermic machine perfusion (TA-NRP). Both approaches could impact lung transplant outcomes with combined heart and lung procurements from the same donor. The impact of such practice on DCD lung transplant remains unstudied. We performed a retrospective analysis using the United Network for Organ Sharing (UNOS) dataset, identifying DCD lung transplants where the donor also donated the heart (cardia lung donor [CD]). A cohort of noncardiac DCD lung donors (noncardiac lung donor [NCD]) from the same era, matched for donor and recipient characteristics, was used as a comparison group. Both immediate and long-term outcomes were examined. A subanalysis was performed comparing the distinct impact of DP or TA-NRP on DCD lung transplant outcomes. Overall graft survival did not significantly differ between CD and NCD. However, recipients in the CD group trended toward a lower P/F ratio at 72 hours (CD vs NCD: 284 vs 3190; P = .054). In the subanalysis, we identified 40 DP donors and 22 TA-NRP donors. We found the both cohorts had lower P/F ratio at 72 hours than the NCD control (P = .04). Overall, 1-year graft survival was equivalent among the TA-NRP, DP, and NCD cohorts.

Despite advancements in surgical treatment, the survival rate of esophageal carcinoma remains suboptimal. 1 Al-Batran S.E. Homann N. Pauligk C. et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019; 393: 1948-1957https://doi.org/10.1016/S0140-6736(18)32557-1 Abstract Full Text Full Text PDF PubMed Scopus (1305) Google Scholar Multiple studies have examined the impact of adding radiotherapy, chemotherapy, or both as adjuvant or neoadjuvant therapies to surgical resection. 1 Al-Batran S.E. Homann N. Pauligk C. et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019; 393: 1948-1957https://doi.org/10.1016/S0140-6736(18)32557-1 Abstract Full Text Full Text PDF PubMed Scopus (1305) Google Scholar One landmark trial was the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study (CROSS) trial, which demonstrated that neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection produced superior results to primary resection alone. 2 van Hagen P. Hulshof M.C.C.M. van Lanschot JJB et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012; 366: 2074-2084https://doi.org/10.1056/NEJMoa1112088 Crossref PubMed Scopus (3969) Google Scholar Patients in the nCRT cohort exhibited improved survival and higher rates of R0 resection compared with primary surgery alone. 2 van Hagen P. Hulshof M.C.C.M. van Lanschot JJB et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012; 366: 2074-2084https://doi.org/10.1056/NEJMoa1112088 Crossref PubMed Scopus (3969) Google Scholar Since the trial’s publication in 2012, nCRT has become the standard of care at many centers worldwide, but some have criticized the results due to strict inclusion criteria that may not reflect what is seen in daily practice. 3 Abraham A.G. Joseph K. Spratlin J.L. et al. Does loosening the inclusion criteria of the CROSS trial impact outcomes in the curative-intent trimodality treatment of oesophageal and gastroesophageal cancer patients?. Clin Oncol. 2022; 34: e369-e376https://doi.org/10.1016/j.clon.2022.05.011 Abstract Full Text Full Text PDF Scopus (2) Google Scholar Primary Surgery Not Inferior to Neoadjuvant Chemoradiotherapy for Esophageal AdenocarcinomaThe Annals of Thoracic SurgeryVol. 116Issue 3PreviewThe current gold standard for treatment of locally advanced esophageal adenocarcinoma is neoadjuvant chemotherapy or chemoradiotherapy followed by surgery. The shift toward neoadjuvant chemoradiotherapy (nCRT) was driven by the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) trial. This study reassessed, in daily practice, the presumed advantage of nCRT followed by surgery on long-term survival compared with primary surgery, in a group of all adenocarcinomas treated through a transthoracic approach with extensive 2-field lymphadenectomy. Full-Text PDF

ObjectivesS100A8/A9 is a damage-associated molecule that augments systemic inflammation. However, its role in the acute phase after lung transplantation (LTx) remains elusive. This study aimed to determine S100A8/A9 levels after lung transplantation (LTx) and evaluate their impact on overall survival (OS) and chronic lung allograft dysfunction (CLAD)-free survival. MethodsSixty patients were enrolled in this study, and their plasma S100A8/A9 levels were measured on days 0, 1, 2, and 3 after LTx. The association of S100A8/A9 levels with OS and CLAD-free survival was assessed using univariate and multivariate Cox regression analyses. ResultsS100A8/A9 levels were elevated in a time-dependent manner until 3 days after LTx. Ischemic time was significantly longer in the high S100A8/9 group than in the low S100A8/A9 group (p = .017). Patients with high S100A8/A9 levels (> 2844 ng/mL) had worse prognosis (p = .031) and shorter CLAD-free survival (p = .045) in the Kaplan-Meier survival analysis than those with low levels. Furthermore, multivariate Cox regression analysis showed that high S100A8/A9 levels were a determinant of poor OS (hazard ratio [HR]: 3.7; 95% confidence interval [CI]: 1.2-12; p = .028) and poor CLAD-free survival (HR: 4.1; 95% CI: 1.1-15; p = .03). In patients with a low primary graft dysfunction grade (0-2), a high level of S100A8/A9 was also a poor prognostic factor. ConclusionsOur study provided novel insights into the role of S100A8/A9 as a prognostic biomarker and a potential therapeutic target for LTx.

Cancer-associated fibroblasts (CAFs) are important components in the tumor microenvironment, and we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). In this study, we established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells. RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we identified that the expression of periostin (POSTN), which is known to be overexpressed in various solid tumors and promote cancer progression, was significantly higher in CAFs than in NFs. POSTN increased cell proliferation via NSCLC cells' ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for osimertinib treatment. Collectively, our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN could be a potential therapeutic strategy for NSCLC. KEY MESSAGES: • POSTN is significantly upregulated in CAFs compared to normal fibroblasts in NCSLC. • POSTN increases cell proliferation via activation of the NSCLC cells' ERK pathway. • POSTN induces EMT in NSCLC cells and improves the migration ability. • POSTN knockdown improves the sensitivity for osimertinib in EGFR-mutant NSCLC cells.

Although bronchiolitis obliterans syndrome (BOS) is a major cause of death after lung transplantation, an effective drug therapy for BOS has not yet developed. Here, we assessed the effectiveness of a neutralizing anti-S100 calcium binding protein (S100) A8/A9 antibody against BOS. A murine model of heterotopic tracheal transplantation was used. Mice were intraperitoneally administered control IgG or the S100A8/A9 antibody on day 0 and twice per week until they were sacrificed. Tissue sections were used to evaluate the obstruction ratio, epithelium-preservation ratio, α-smooth muscle actin (SMA)-positive myofibroblast infiltration, and luminal cell death. Quantitative reverse transcriptase-polymerase chain reaction analysis was performed to analyze the mRNA-expression levels of collagen, inflammatory cytokines, and chemokines on days 7, 14, and 21. The anti-S100A8/A9 antibody significantly improved the obstruction ratio and epithelium-preservation ratio, with less α-SMA-positive myofibroblast infiltration compared to the control group. Antibody treatment reduced the type-III collagen: type-I collagen gene-expression ratio. The antibody also significantly suppressed the number of dead cells in the graft lumen. The expression levels of tumor growth factor β1 and C–C motif chemokine 2 on day 21, but not those of interleukin-1β, interleukin-6, and tumor necrosis factor α, were significantly suppressed by S100A8/A9 antibody treatment. These findings suggest that S100A8/A9 may be a potential therapeutic target for BOS after lung transplantation.

(1) Background: Lung ischemia–reperfusion (IR) injury increases the mortality and morbidity of patients undergoing lung transplantation. The objective of this study was to identify the key initiator of lung IR injury and to evaluate pharmacological therapeutic approaches using a functional inhibitor against the identified molecule. (2) Methods: Using a mouse hilar clamp model, the combination of RNA sequencing and histological investigations revealed that neutrophil-derived S100A8/A9 plays a central role in inflammatory reactions during lung IR injury. Mice were assigned to sham and IR groups with or without the injection of anti-S100A8/A9 neutralizing monoclonal antibody (mAb). (3) Results: Anti-S100A8/A9 mAb treatment significantly attenuated plasma S100A8/A9 levels compared with control IgG. As evaluated by oxygenation capacity and neutrophil infiltration, the antibody treatment dramatically ameliorated the IR injury. The gene expression levels of cytokines and chemokines induced by IR injury were significantly reduced by the neutralizing antibody. Furthermore, the antibody treatment significantly reduced TUNEL-positive cells, indicating the presence of apoptotic cells. (4) Conclusions: We identified S100A8/A9 as a novel therapeutic target against lung IR injury.