Lung Ischemia-reperfusion Injury Research Articles

Penehyclidine hydrochloride alleviates lung ischemia-reperfusion injury by inhibiting pyroptosis

ObjectiveThe aim of this research was to examine how penehyclidine hydrochloride (PHC) impacts the occurrence of pyroptosis in lung tissue cells within a rat model of lung ischemia-reperfusion injury.MethodsTwenty-four Sprague Dawley (SD) rats, weighing 250 g to 270 g, were randomly distributed into three distinct groups as outlined below: a sham operation group (S group), a control group (C group), and a test group (PHC group). Rats in the PHC group received a preliminary intravenous injection of PHC at a dose of 3 mg/kg. At the conclusion of the experiment, lung tissue and blood samples were collected and properly stored for subsequent analysis. The levels of malondialdehyde, superoxide dismutase, and myeloperoxidase in the lung tissue, as well as IL-18 and IL-1β in the blood serum, were assessed using an Elisa kit. Pyroptosis-related proteins, including Caspase1 p20, GSDMD-N, and NLRP3, were detected through the western blot method. Additionally, the dry-to-wet ratio (D/W) of the lung tissue and the findings from the blood gas analysis were also documented.ResultsIn contrast to the control group, the PHC group showed enhancements in oxygenation metrics, reductions in oxidative stress and inflammatory reactions, and a decrease in lung injury. Additionally, the PHC group exhibited lowered levels of pyroptosis-associated proteins, including the N-terminal segment of gasdermin D (GSDMD-N), caspase-1p20, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3).ConclusionPre-administration of PHC has the potential to mitigate lung ischemia-reperfusion injuries by suppressing the pyroptosis of lung tissue cells, diminishing inflammatory reactions, and enhancing lung function. The primary mechanism behind anti-pyroptotic effect of PHC appears to involve the inhibition of oxidative stress.

Murine Left Pulmonary Hilar Clamp Model of Lung Ischemia Reperfusion Injury.

Ischemia reperfusion injury (IRI) during lung transplantation is a major risk factor for post-transplant complications, including primary graft dysfunction, acute and chronic rejection, and mortality. Efforts to study the underpinnings of IRI led to the development of a reliable and reproducible mouse model of left lung hilar clamping. This model involves a surgical procedure performed in an anesthetized and intubated mouse. A left thoracotomy is performed, followed by careful lung mobilization and dissection of the left pulmonary hilum. The hilar clamp involves reversible suture ligation of the pulmonary hilum with a slipknot, which stops the arterial inflow, venous outflow, and airflow through the left mainstem bronchus. Reperfusion is initiated by careful removal of the suture. Our laboratory uses 30 min of ischemia and 1 h of reperfusion for the experimental model in the current investigations. However, these time periods can be modified depending on the specific experimental question. Immediately prior to sacrifice, arterial blood gas can be obtained from the left ventricle after a 4 min period of right hilar clamping to ensure that the PaO2 values obtained are attributed to the injured left lung alone. We also describe a method to measure cell extravasation with flow cytometry, which involves intravenous injection of a fluorochrome-labeled antibody specific for the cell(s) to be studied prior to sacrifice. The left lung can then be harvested for flow cytometry, frozen or fixed, paraffin-embedded immunohistochemistry, and quantitative polymerase chain reaction. This hilar clamp technique allows fordetailed study of the cellular and molecular mechanisms underlying IRI. Representative results reveal decreased left lung oxygenation and histologic evidence of lung injury following hilar clamping. This technique can be readily learned and reproduced by personnel with and without microsurgical experience, leading to reliable and consistent results and serving as a widely adoptable model for studying lung IRI.

Lung Ischemia Reperfusion Injury as a Complication of Pulmonary Thrombectomy

Lung Ischemia Reperfusion Injury as a Complication of Pulmonary Thrombectomy

Rebaudioside B Attenuates Lung Ischemia-reperfusion Injury-associated Apoptosis and Inflammation.

At present, no proven effective treatment is available for Lung Ischemiareperfusion Injury (LIRI). Natural compounds offer promising prospects for developing new drugs to address various diseases. This study sought to explore the potential of Rebaudioside B (Reb B) as a treatment compound for LIRI, both in vivo and in vitro. This study involved utilizing the human pulmonary alveolar cell line A549, consisting of epithelial type II cells, subjected to Oxygen-glucose Deprivation/recovery (OGD/R) for highthroughput in vitro cell viability screening. The aim was to identify the most promising candidate compounds. Additionally, an in vivo rat model of lung ischemia-reperfusion was employed to evaluate the potential protective effects of Reb B. Through high-throughput screening, Reb B emerged as the most promising natural compound among those tested. In the A549 OGD/R models, Reb B exhibited a capacity to enhance cell viability by mitigating apoptosis. In the in vivo LIRI model, pre-treatment with Reb B notably decreased apoptotic cells, perivascular edema, and neutrophil infiltration within lung tissues. Furthermore, Reb B demonstrated its ability to attenuate lung inflammation associated with LIRI primarily by elevating IL-10 levels while reducing levels of IL-6, IL-8, and TNF-α. The comprehensive outcomes strongly suggest Reb B's potential as a protective agent against LIRI. This effect is attributed to its inhibition of the mitochondrial apoptotic pathway and its ability to mitigate the inflammatory response.

(598) - The Effect of Resolvin D1, Resolvin E1, and Their Precursors on Lung Ischemia-Reperfusion Injury

(598) - The Effect of Resolvin D1, Resolvin E1, and Their Precursors on Lung Ischemia-Reperfusion Injury

Transient receptor potential vanilloid 4 channel inhibition attenuates lung ischemia-reperfusion injury in a porcine lung transplant model.

Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel important in many physiological and pathophysiological processes, including pulmonary disease. Using a murine model, we previously demonstrated that TRPV4 mediates lung ischemia-reperfusion injury, the major cause of primary graft dysfunction after transplant. The current study tests the hypothesis that treatment with a TRPV4 inhibitor will attenuate lung ischemia-reperfusion injury in a clinically relevant porcine lung transplant model. A porcine left-lung transplant model was used. Animals were randomized to 2 treatment groups (n=5/group): vehicle or GSK2193874 (selective TRPV4 inhibitor). Donor lungs underwent 30minutes of warm ischemia and 24hours of cold preservation before left lung allotransplantation and 4hours of reperfusion. Vehicle or GSK2193874 (1mg/kg) was administered to the recipient as a systemic infusion after recipient lung explant. Lung function, injury, and inflammatory biomarkers were compared. After transplant, left lung oxygenation was significantly improved in the TRPV4 inhibitor group after 3 and 4hours of reperfusion. Lung histology scores and edema were significantly improved, and neutrophil infiltration was significantly reduced in the TRPV4 inhibitor group. TRPV4 inhibitor-treated recipients had significantly reduced expression of interleukin-8, high mobility group box 1, P-selectin, and tight junction proteins (occludin, claudin-5, and zonula occludens-1) in bronchoalveolar lavage fluid as well as reduced angiopoietin-2 in plasma, all indicative of preservation of endothelial barrier function. Treatment of lung transplant recipients with TRPV4 inhibitor significantly improves lung function and attenuates ischemia-reperfusion injury. Thus, selective TRPV4 inhibition may be a promising therapeutic strategy to prevent primary graft dysfunction after transplant.

(269) - Inhibition of ALOX12-12-HETE Alleviates Lung Ischemia Reperfusion Injury by Reducing Endothelial Ferroptosis-Mediated Neutrophil Extracellular Traps Formation

(269) - Inhibition of ALOX12-12-HETE Alleviates Lung Ischemia Reperfusion Injury by Reducing Endothelial Ferroptosis-Mediated Neutrophil Extracellular Traps Formation

(660) - Protective Effect of Club Cell Secretory Protein (CCSP) in Mouse Lung Ischemia Reperfusion Injury

(660) - Protective Effect of Club Cell Secretory Protein (CCSP) in Mouse Lung Ischemia Reperfusion Injury

(664) - MerTK-Dependent Efferocytosis by Monocytic MDSCs Contributes to the Resolution of Lung Ischemia-Reperfusion Injury

(664) - MerTK-Dependent Efferocytosis by Monocytic MDSCs Contributes to the Resolution of Lung Ischemia-Reperfusion Injury

Erythropoietin alleviates lung ischemia-reperfusion injury by activating the FGF23/FGFR4/ERK signaling pathway.

The purpose of the present study was to investigate the effect of erythropoietin (EPO) on lung ischemia-reperfusion injury (LIRI). Sprague Dawley rats and BEAS-2B cells were employed to construct an ischemia-reperfusion (I/R)-induced model in vivo and in vitro, respectively. Afterward, I/R rats and tert-butyl hydroperoxide (TBHP)-induced cells were treated with different concentrations of EPO. Furthermore, 40 patients with LIRI and healthy controls were enrolled in the study. It was observed that lung tissue damage, cell apoptosis and the expression of BAX and caspase-3 were higher in the LIRI model in vivo and in vitro than in the control group, nevertheless, the Bcl-2, FGF23 and FGFR4 expression level was lower than in the control group. EPO administration significantly reduced lung tissue damage and cell apoptosis while also up-regulating the expression of FGF23 and FGFR4. Rescue experiments indicated that EPO exerted a protective role associated with the FGF23/FGFR4/p-ERK1/2 signal pathway. Notably, the expression of serum EPO, FGF23, FGFR4 and Bcl-2 was decreased in patients with LIRI, while the expression of caspase-3 and BAX was higher. EPO could effectively improve LIRI, which might be related to the activation of the FGF23/FGFR4/p-ERK1/2 signaling pathway.

Nanoparticle targeting of neutrophil glycolysis prevents lung ischemia-reperfusion injury

Neutrophils exacerbate pulmonary ischemia-reperfusion injury (IRI) resulting in poor short and long-term outcomes for lung transplant recipients. Glycolysis powers neutrophil activation, but it remains unclear if neutrophil-specific targeting of this pathway will inhibit IRI. Lipid nanoparticles containing the glycolysis flux inhibitor 2-deoxyglucose (2-DG) were conjugated to neutrophil-specific Ly6G antibodies (NP-Ly6G[2-DG]). Intravenously administered NP-Ly6G(2-DG) to mice exhibited high specificity for circulating neutrophils. NP-Ly6G(2-DG)–treated neutrophils were unable to adapt to hypoglycemic conditions of the lung airspace environment as evident by the loss of demand-induced glycolysis, reductions in glycogen and ATP content, and an increased vulnerability to apoptosis. NP-Ly6G(2-DG) treatment inhibited pulmonary IRI following hilar occlusion and orthotopic lung transplantation. IRI protection was associated with less airspace neutrophil extracellular trap generation, reduced intragraft neutrophilia, and enhanced alveolar macrophage efferocytotic clearance of neutrophils. Collectively, our data show that pharmacologically targeting glycolysis in neutrophils inhibits their activation and survival leading to reduced pulmonary IRI.

High Dose ofEstrogen Protects the Lungs from Ischemia-Reperfusion Injury by Downregulating the Angiotensin II Signaling Pathway.

We explored the sex difference in lung ischemia-reperfusion injury (LIRI) and the role and mechanism of estrogen (E2) and angiotensin II (Ang II) in LIRI. We established a model of LIRI in mice. E2, Ang II, E2 inhibitor (fulvestrant), and angiotensin II receptor blocker (losartan) were grouped for treatment. The lung wet/dry weight ratio, natural killer (NK) cells (by flow cytometry), neutrophils (by flow cytometry), expression of key proteins (by Western blot, immunohistochemistry, ELISA, and immunofluorescence), and expression of related protein mRNA (by qPCR) were detected. The ultrastructure of the alveolar epithelial cells was observed by transmission electron microscopy. We found that E2 and Ang II played an important role in the progression of LIRI. The two signaling pathways showed obvious antagonism, and E2 regulates LIRI in the different sexes by downregulating Ang II, leading to a better prognosis. E2 and losartan reduced the inflammatory cell infiltration in lung tissue and key inflammatory factors in serum while fulvestrant and Ang II had the opposite effect. The protective effect of E2 was related with AKT, p38, COX2, and HIF-1α.

Tocilizumab Reduces Lung Injury in a Rat Lung Ischemia and Reperfusion Model.

In this study, the effect of tocilizumab (TCZ) on lung tissue in lung ischemia-reperfusion (I/R) injury in rats was investigated. A total of 24 Wistar rats were divided into 4 equal groups, with 6 rats in each group: Left lung I/R was applied to I/R groups. In the I/R groups, the left lung hilum was clamped for 45 minutes, and then the clamp was removed and reperfused for 120 minutes. In the TCZ groups, 4 mg/kg and 8 mg/kg of TCZ were administered intraperitoneally to the rats 30 minutes before surgery. The tumor necrosis factor-alpha mean value was not statistically significant between the groups (P = .091). Statistically significant results were observed between group I/R-TCZ (8 mg/kg) and group I/R for catalase. (P = .005). Statistically significant results were observed between group I/R-TCZ (8 mg/kg) and group I/R for malondialdehyde. (P = .009). The difference in total ischemia score between group I/R-TCZ (4 mg/kg) and group I/R-TCZ (8 mg/kg) and group I/R was statistically significant (P < .001). In terms of alveolar hemorrhage, there was a statistically significant difference between group I/R-TCZ (4 mg/kg) and group I/R-TCZ (8 mg/kg) and group I/R (P = .01 and P = .002, respectively). There was a statistically significant difference between group I/R-TCZ (8 mg/kg) and group I/R in terms of neutrophil accumulation (P = .01). In terms of interstitial edema, there was a statistically significant difference between group I/R-TCZ (4 mg/kg) and group I/R-TCZ (8 mg/kg) and group I/R (P = .006 and P = .001, respectively). In terms of pulmonary edema, there was a statistically significant difference between group I/R-TCZ (4 mg/kg) and group I/R-TCZ (8 mg/kg) and group I/R (P = .01 and P = .009, respectively). Lung tissue may be affected by I/R injury and this damage can be reversed with the use of TCZ.

Metformin alleviates lung ischemia–reperfusion injury in a rat lung transplantation model

Background: Lung ischemia–reperfusion injury (LIRI) is among the complications observed after lung transplantation and is associated with morbidity and mortality. Preconditioning of the donor lung before organ retrieval may improve organ quality after transplantation. We investigated whether preconditioning with metformin (Met) ameliorates LIRI after lung transplantation. Methods: Twenty Lewis rats were randomly divided into the sham, LIRI, and Met groups. The rats in the LIRI and Met groups received saline and Met, respectively, via oral gavage. Subsequently, a donor lung was harvested and kept in cold storage for 8 h. The LIRI and Met groups then underwent left lung transplantation. After 2 h of reperfusion, serum and transplanted lung tissues were examined. Results: The partial pressure of oxygen (PaO2) was greater in the Met group than in the LIRI group. In the Met group, wet-to-dry (W/D) weight ratios, inflammatory factor levels, oxidative stress levels and apoptosis levels were notably decreased. Conclusions: Met protects against ischemia–reperfusion injury after lung transplantation in rats, and its therapeutic effect is associated with its anti-inflammatory, antioxidative, and antiapoptotic properties.

A Novel Peroxisome Proliferator-Activated Receptor Gamma/Nuclear Factor-Kappa B Activation Pathway is Involved in the Protective Effect of Adipose-Derived Mesenchymal Stem Cells Against Ischemia-Reperfusion Lung Injury

BackgroundAdipose-derived stem cells (ADSCs) are well-recognized for their remarkable ability to suppress ischemia-reperfusion lung injury (IRLI). The primary objective of this investigation was to elucidate the underlying mechanism through which ADSCs exert protective effects against IRLI. MethodsA warm hilar occlusion model in C57BL6J mice was used. Hilar occlusion was achieved for 1 h (ischemic) and after 1 h, the occlusion was released (reperfusion) to recover for 3 h. RNA sequencing, the physiological function, pathway activation, and expression of inflammatory cytokines were evaluated. ResultsLung gas exchange and pulmonary edema were significantly improved in the IRLI/ADSCs group compared to the IRLI group. RNA sequencing results suggested that the peroxisome proliferator-activated receptor gamma (PPARγ)/nuclear factor-kappa B (NF-κB) pathway was involved in the effect of the ADSCs. Administration of a PPARγ antagonist in the IRLI/ADSC group resulted in the deterioration of the physiological function . Furthermore, the PPARγ protein expression level decreased, the NF-κB protein expression level increased and inflammatory cytokine parameters from lung tissue and blood sample worsened in the PPARγ antagonist-administered group. ConclusionAdministration of ADSCs exerted a significant protective effect against IRLI in mice, and the effect is attributed to the activation of the PPARγ/NF-κB pathway.

Advances in lung ischemia/reperfusion injury: unraveling the role of innate immunity.

Lung ischemia/reperfusion injury (LIRI) is a common occurrence in clinical practice and represents a significant complication following pulmonary transplantation and various diseases. At the core of pulmonary ischemia/reperfusion injury lies sterile inflammation, where the innate immune response plays a pivotal role. This review aims to investigate recent advancements in comprehending the role of innate immunity in LIRI. A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning lung ischemia/reperfusion injury, cell death, damage-associated molecular pattern molecules (DAMPs), innate immune cells, innate immunity, inflammation. During the process of lung ischemia/reperfusion, cellular injury even death can occur. When cells are injured or undergo cell death, endogenous ligands known as DAMPs are released. These molecules can be recognized and bound by pattern recognition receptors (PRRs), leading to the recruitment and activation of innate immune cells. Subsequently, a cascade of inflammatory responses is triggered, ultimately exacerbating pulmonary injury. These steps are complex and interrelated rather than being in a linear relationship. In recent years, significant progress has been made in understanding the immunological mechanisms of LIRI, involving novel types of cell death, the ability of receptors other than PRRs to recognize DAMPs, and a more detailed mechanism of action of innate immune cells in ischemia/reperfusion injury (IRI), laying the groundwork for the development of novel diagnostic and therapeutic approaches. Various immune components of the innate immune system play critical roles in lung injury after ischemia/reperfusion. Preventing cell death and the release of DAMPs, interrupting DAMPs receptor interactions, disrupting intracellular inflammatory signaling pathways, and minimizing immune cell recruitment are essential for lung protection in LIRI.

Piezo1 mediates abnormal type 2 immune response to aggravate ischemia–reperfusion acute lung injury which by regulating alveolar macrophages derived IL-33: A hypothesis

The pathogenesis of ischemia–reperfusion acute lung injury (IR-ALI) is not yet fully understood. We previously reported that unwonted increased type 2 immunity plays a key role in the pathogenesis and the pathophysiological process in acute haemorrhagic inducedlung injury. Progressive lung edema after ischemia reperfusion is accompanied by the change of lung cyclical hydrostatic force. The changed lung mechanical force could activate the mechanosensitive Piezo1 channel in alveolar macrophages. Furthermore, our group had elucidated that microenvironmental stiffness exacerbated hindlimb ischemia reperfusion injury by activating Piezo1 in bone marrow-derived macrophages. Considering early findings that IL-33 is a potent driver of pulmonary type 2 immunity, that Piezo1 plays an important role in regulating macrophages biological activity and that alveolar macrophages are involved in orchestrating the early abnormal detrimental type 2 inflammatory response in lung ischemia–reperfusion injury, we herein hypothesize that the change of mechanical force in lung after ischemia–reperfusion might activate Piezo1/IL-33/type 2 immunity axis and aggravate lung ischemic injury. Mechanistically, Piezo1 mediates extracellular Ca2+influx and activates Ca2+-dependent Calcineurin-NFAT signaling in alveolar macrophages, leading to transcriptional activation of IL-33, thereby promoting abnormal type 2 immune response and participating in the occurrence and development of IR-ALI. Future validation of these mechanisms could provide a deeper explanation of the new pathogenesis of IR-ALI and ultimately serve for clinical treatment.

Retracted: KGF-2 Protects against Lung Ischemia-Reperfusion Injury by Inhibiting Inflammation-Induced Damage to Endothelial Barrier Function.

[This retracts the article DOI: 10.1155/2022/3055039.].

Hydroxycitric Acid Alleviated Lung Ischemia-Reperfusion Injury by Inhibiting Oxidative Stress and Ferroptosis through the Hif-1α Pathway.

Lung ischemia-reperfusion injury (LIRI) is a prevalent occurrence in various pulmonary diseases and surgical procedures, including lung resections and transplantation. LIRI can result in systemic hypoxemia and multi-organ failure. Hydroxycitric acid (HCA), the primary acid present in the peel of Garcinia cambogia, exhibits anti-inflammatory, antioxidant, and anticancer properties. However, the effects of HCA on LIRI remain unknown. To investigate the impact of HCA on LIRI in mice, the mice were randomly divided into four groups: the control group, the I/R model group, and the I/R + low- or high-dose HCA groups. Human umbilical vein endothelial cells (HUVECs) were subjected to hypoxia for 12 h followed by reoxygenation for 6 h to simulate in vitro LIRI. The results demonstrated that administration of HCA effectively attenuated lung injury, inflammation, and edema induced by ischemia reperfusion. Moreover, HCA treatment significantly reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels while decreasing iron content and increasing superoxide dismutase (SOD) levels after ischemia-reperfusion insult. Mechanistically, HCA administration significantly inhibited Hif-1α and HO-1 upregulation both in vivo and in vitro. We found that HCA could also alleviate endothelial barrier damage in H/R-induced HUVECs in a concentration-dependent manner. In addition, overexpression of Hif-1α counteracted HCA-mediated inhibition of H/R-induced endothelial cell ferroptosis. In summary, these results indicate that HCA alleviated LIRI by inhibiting oxidative stress and ferroptosis through the Hif-1α pathway.

β-aminoisobutyrics acid, a metabolite of BCAA, activates the AMPK/Nrf-2 pathway to prevent ferroptosis and ameliorates lung ischemia-reperfusion injury

BackgroundLung ischemia-reperfusion (I/R) injury is a serious clinical problem without effective treatment. Enhancing branched-chain amino acids (BCAA) metabolism can protect against cardiac I/R injury, which may be related to bioactive molecules generated by BCAA metabolites. L-β-aminoisobutyric acid (L-BAIBA), a metabolite of BCAA, has multi-organ protective effects, but whether it protects against lung I/R injury is unclear.MethodsTo assess the protective effect of L-BAIBA against lung I/R injury, an animal model was generated by clamping the hilum of the left lung, followed by releasing the clamp in C57BL/6 mice. Mice with lung I/R injury were pre-treated or post-treated with L-BAIBA (150 mg/kg/day), given by gavage or intraperitoneal injection. Lung injury was assessed by measuring lung edema and analyzing blood gases. Inflammation was assessed by measuring proinflammatory cytokines in bronchoalveolar lavage fluid (BALF), and neutrophil infiltration of the lung was measured by myeloperoxidase activity. Molecular biological methods, including western blot and immunofluorescence, were used to detect potential signaling mechanisms in A549 and BEAS-2B cells.ResultsWe found that L-BAIBA can protect the lung from I/R injury by inhibiting ferroptosis, which depends on the up-regulation of the expressions of GPX4 and SLC7A11 in C57BL/6 mice. Additionally, we demonstrated that the Nrf-2 signaling pathway is key to the inhibitory effect of L-BAIBA on ferroptosis in A549 and BEAS-2B cells. L-BAIBA can induce the nuclear translocation of Nrf-2. Interfering with the expression of Nrf-2 eliminated the protective effect of L-BAIBA on ferroptosis. A screening of potential signaling pathways revealed that L-BAIBA can increase the phosphorylation of AMPK, and compound C can block the Nrf-2 nuclear translocation induced by L-BAIBA. The presence of compound C also blocked the protective effects of L-BAIBA on lung I/R injury in C57BL/6 mice.ConclusionsOur study showed that L-BAIBA protects against lung I/R injury via the AMPK/Nrf-2 signaling pathway, which could be a therapeutic target.