Onset of Inflammation With Ischemia: Implications for Donor Lung Preservation and Transplant Survival

Tao, Jianmin; Sorokina, Elena M.; Vázquez‐Medina, José Pablo; Mishra, Manoj K.; Yamada, Yoshito; Satalin, Joshua; Nieman, Gary F.; Nellen, James R.; Beduhn, Ben; Cantu, Edward; Habashi, Nader M.; Jungraithmayr, Wolfgang; Christie, Jason D.; Chatterjee, Shampa

doi:10.1111/ajt.13794

Cited by 24 publications

(39 citation statements)

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“…The major CAMs found on the surface of endothelial cells in injured tissue are the intercellular adhesion molecule (ICAM or CD54) and the vascular endothelial cell adhesion molecule (VCAM or CD106) [31,32] . We observed that the expression of CAMs that facilitate PMN-endothelial cell binding, are ischemia-ROS regulated ( Figure 2) [19,25] . Besides CAMs, there is hypoxiainducible factor 1α (HIF-1α), which transcriptionally regulates a host of inflammatory cytokines [33] .…”

Section: Introductionmentioning

confidence: 88%

“…We reported earlier that with loss of flow, the pulmonary endothelium in situ and endothelial cells in vitro(in flow chambers that mimic blood vessels) are activated via a KATP channel-NADPH oxidase 2 signaling pathway that causes the production of ROS (Figure 1) [18,21] . ROS production was evaluated from oxidation of various ROS-sensitive fluorescence dyes [dihydroethidine (DHE) for superoxide anion, dichlorofluorescein (DCF) for H2O2, and Amplex red (for intravascular H2O2)] [16,19,21] . ROS production that follows the ischemia signaling cascade that as we reported earlier, involves the "sensing" of the loss of flow stimulus by a complex machinery (for which we coined the term mechanosome) comprising of several elements namely caveolae and platelet endothelial cell adhesion molecule -1 (PECAM-1) [21] along with presumably other moieties like vascular endothelial growth factor receptor 2 (VEGFR-2) as reported by others [22] .…”

Section: New Strategies and Emerging Therapies For Lung Preservationmentioning

confidence: 99%

“…ROS is a term that encompasses various free radicals, ions and reactive species that are generated by enzymatic and non-enzymatic sources in various cell types. The ROS produced with lung storage or ischemia activates an inflammation cascade that besides damaging the stored lungs could potentially affect the graft post-transplant [19] . Thus blocking ischemia induced signaling in the donor lung would increase viability of lungs during storage and would by minimizing inflammation signals reduce the influx of PMN from the recipient post-transplant.…”

Section: Introductionmentioning

confidence: 99%

“…macrophages, mast cells) from the recipient's circulation post-transplant [34,35] . ROS produced with ischemia regulates both HIF-1α and VEGF and may account for revascularization in the vasculature [19,26] or onset of inflammation in situ as observed in human donor lungs [19] . Increase in the DAMP protein high-mobility group box 1 (HMGB1) and increased expression of its PRR, receptor for advanced glycation end products (RAGE), are critical in onset and amplification of inflammation and have been implicated in numerous inflammation pathologies including I/R and endotoxemia [36,37] .…”

Section: Introductionmentioning

confidence: 99%

“…showed that lung storage led to increased induction of both HMGB1 and RAGE [19] . HMGB1-RAGE axis is part of a coordinated response that cells use to trigger inflammatory cascades by driving assembly of Nod-like Receptor Protein 3 (NLRP3) inflammasomes [38] .…”

Section: Introductionmentioning

confidence: 99%

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Focusing on Donor Lung Organ Storage: Implications for Inflammation Post-Transplant

Jungraithmayr¹,

Gupta²,

Chatterjee³

2016

Journal of Respiratory Research

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polymorphonuclear neutrophils (PMN) are recruited to and adhere to the endothelium of the lung, transmigrate and release reactive oxygen species (ROS). Recognizing the role of PMN in poor transplant outcome, the clinical strategy at present is to block PMN activation by a non-specific immunosuppression regimen administered to the transplant recipient. As immunosuppression therapy has severe side effects, alternate means of blocking and inhibiting inflammation in the lung are being considered. The binding of PMN to the endothelium is a prerequisite of inflammation; thus our research is focused on the endothelium of the donor lung so as to block endothelial signals that facilitate its binding to PMN. Such a strategy of inhibiting the moieties on the vascular wall so that as prevent donor lung endothelial interaction with the recipient's PMN is an early intervention and has the potential to prevent injury completely. In contrast, immunosuppression involves minimizing influx and recruitment of PMN and immune cells after the initial adherence and binding that would take place immediately upon transplant. Our extensive work on lung storage or ischemia shows that the pulmonary endothelium responds to stop of blood flow by a signaling cascade that involves KATP channel closure, PI3Kinase activation and assembly of the enzyme NADPH oxidase 2 (NOX2) leading to the generation of ROS. We found that the ROS thus produced triggers the onset of an inflammation cascade during the storage period itself, ahead of the transplant event. Onset of inflammation causes damage to the donor lung during storage thus affecting donor lung availability; additionally it can potentially drive immune cell recruitment via inflamed lung vessel wall. Thus optimal storage conditions such as keeping the lung (organ) perfused or inhibiting ischemia induced signaling by blocking KATP closure, PI3K activation or NOX2 assembly may potentially preserve lung viability and minimize inflammation and injury post-transplant. ABSTRACTLung transplantation is a surgical option to replace a diseased lung with a healthy lung from a donor. This surgical process causes stop of blood flow from the point of organ retrieval or procurement followed by cold and warm storage phase (ischemia), followed by the reinstatement of blood flow with implantation (reperfusion) that occurs upon transplant. The injury incurred during ischemia (retrieval and storage) together with the injury from reperfusion (I/R injury) is considered as the main driver of onset of primary graft dysfunction (PGD). PGD is a multifactorial injury that is characterized by cellular infiltrates and severe oxidative damage; it occurs within 24 h posttransplant and is a critical factor in determining transplant outcome. PGD occurs in large part due to inflammation post-transplant when EDITORIAL Focusing on Donor Lung Journal of Respiratory Researchchallenge with transplant is allograft rejection that occurs when T lymphocytes from the recipient recognize non-self forms of class I and class II major histoco...

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Section: Introductionmentioning

confidence: 88%

Section: New Strategies and Emerging Therapies For Lung Preservationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Focusing on Donor Lung Organ Storage: Implications for Inflammation Post-Transplant

Jungraithmayr¹,

Gupta²,

Chatterjee³

2016

Journal of Respiratory Research

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Sterile inflammation in thoracic transplantation

Frye

Bery

Kreisel

et al. 2020

Cell. Mol. Life Sci.

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The Amide Local Anesthetic Ropivacaine Attenuates Acute Rejection After Allogeneic Mouse Lung Transplantation

Maeyashiki

Jang

Janker

et al. 2019

Lung

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Purpose Acute allograft rejection after lung transplantation remains an unsolved hurdle. The pathogenesis includes an inflammatory response during and after transplantation. Ropivacaine, an amide-linked local anesthetic, has been shown to attenuate lung injury due to its anti-inflammatory effects. We hypothesized that the drug would also be able to attenuate acute rejection (AR) after allogeneic lung transplantation. Methods Allogeneic, orthotopic, single left lung transplantation was performed between BALB/c (donors) and C57BL/6 (recipients) mice. Prior to explantation, lungs were flushed with normal saline with or without ropivacaine (final concentration 1 µM). Plasma levels of tumor necrosis factor-α and interleukins − 6 and − 10 were measured 3 h after transplantation by ELISA. Lung function was assessed on postoperative day five and transplanted lungs were analyzed using histology (AR), immunohistochemistry (infiltrating leukocytes) and Western blot (phosphorylation and expression of Src and caveolin-1). Results Ropivacaine pre-treatment significantly reduced AR scores (median 3 [minimum-maximum 2-4] for control vs. 2 [1-2] for ropivacaine, p < 0.001) and plasma levels of tumor necrosis factor-α (p = 0.01) compared to control, whereas plasma concentrations of interleukin − 6 (p = 0.008) and − 10 (p < 0.001) were increased by ropivacaine. The number of T-lymphocytes infiltrating the transplanted lung was attenuated (p = 0.02), while no differences in macrophage or B-lymphocyte numbers could be observed after ropivacaine pre-treatment. Caveolin-1 phosphorylation in ropivacaine-treated lungs was diminished (p = 0.004). Conclusions Pre-treatment of donor lungs with the local anesthetic ropivacaine diminished histological signs of AR after orthotopic left lung transplantation in mice, most likely due to reduced infiltration of T-lymphocytes into the graft.

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Onset of Inflammation With Ischemia: Implications for Donor Lung Preservation and Transplant Survival

Cited by 24 publications

References 65 publications

Focusing on Donor Lung Organ Storage: Implications for Inflammation Post-Transplant

Focusing on Donor Lung Organ Storage: Implications for Inflammation Post-Transplant

Sterile inflammation in thoracic transplantation

The Amide Local Anesthetic Ropivacaine Attenuates Acute Rejection After Allogeneic Mouse Lung Transplantation

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