Pulmonary inflammation after lung transplantation

Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA.
Surgery (Impact Factor: 3.11). 08/2009; 146(1):1-4. DOI: 10.1016/j.surg.2009.02.011
Source: PubMed
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    ABSTRACT: Acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) can result from both direct and indirect pulmonary damage caused by trauma and shock. In the course of ALI/ARDS, mediators released from resident cells, such as alveolar macrophages, may act as chemoattractants for invading cells and stimulate local cells to build up a pro-inflammatory micro-milieu. Depending on the trauma setting, the role of alveolar macrophages is differentially defined. This review focuses on alveolar macrophage function after blunt chest trauma, ischemia/reperfusion, hemorrhagic shock and thermal burns.
    Shock (Augusta, Ga.) 03/2014; 42(1). DOI:10.1097/SHK.0000000000000167 · 2.73 Impact Factor
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    ABSTRACT: BACKGROUND: Hypoxia-reoxygenation of cultured macrovascular endothelial cells is used to study ischemia-reperfusion (IR)-related cellular and molecular changes; however, these models do not accurately depict events in pulmonary microvascular endothelial cells (PMVECs) during conventional lung retrieval and transplantation. We used rat PMVECs in a new non-hypoxic cell-based lung transplantation model to assess these events. METHODS: To simulate cold storage, rat PMVECs were preserved in 95% O2-5% CO2 at 4°C for 6 hours in low-potassium dextran solution. Dishes were warmed for 1 hour to room temperature for simulating implantation. Medium was added at 37°C in 50% O2-5% CO2-45% N2 to simulate reperfusion. Additional PMVECs were transfected with siRNA targeting mitogen-activated protein kinases (MAPKs) and then subjected to simulated IR. RESULTS: MAPKs and NF-κB were activated during simulated reperfusion, and AP-1 was activated during ischemia and reperfusion. Increased malondialdehyde levels were found during cold ischemia, and apoptosis and production of IL-1β, IL-6, and TNF-α were observed during reperfusion. Silencing of MAPKs attenuated oxidative stress, inflammation and apoptosis. Silencing of JNK and p38 decreased NF-κB phosphorylation and increased inhibitor of NF-κB (IκB)α levels. Knockdown of ERK1/2 increased NF-κB phosphorylation but had no effect on IκBα expression. Silencing of JNK and ERK1/2, but not p38, decreased AP-1 phosphorylation. CONCLUSIONS: Exposing rat PMVECs to simulated non-hypoxic IR caused lipid peroxidation, inflammation and apoptosis, which required MAPK-mediated NF-κB and AP-1 activation and distinct regulation of MAPKs by these 2 transcription factors. This model could be used to uncouple mechanisms of IR and evaluate potential therapeutics in alleviating IR injury.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 06/2013; 32(8). DOI:10.1016/j.healun.2013.05.005 · 5.61 Impact Factor
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    ABSTRACT: OBJECTIVES: Ischemia-reperfusion injury contributes significantly to morbidity and mortality in lung transplant patients. Currently, no therapeutic agents are clinically available to prevent ischemia-reperfusion injury, and treatment strategies are limited to maintaining oxygenation and lung function. Adenosine can modulate inflammatory activity and injury by binding to various adenosine receptors; however, the role of the adenosine A(1) receptor in ischemia-reperfusion injury and inflammation is not well understood. The present study tested the hypothesis that selective, exogenous activation of the A(1) receptor would be anti-inflammatory and attenuate lung ischemia-reperfusion injury. METHODS: Wild-type and A(1) receptor knockout mice underwent 1 hour of left lung ischemia and 2 hours of reperfusion using an in vivo hilar clamp model. An A(1) receptor agonist, 2-chloro-N6-cyclopentyladenosine, was administered 5 minutes before ischemia. After reperfusion, lung function was evaluated by measuring airway resistance, pulmonary compliance, and pulmonary artery pressure. The wet/dry weight ratio was used to assess edema. The myeloperoxidase and cytokine levels in bronchoalveolar lavage fluid were measured to determine the presence of neutrophil infiltration and inflammation. RESULTS: In the wild-type mice, 2-chloro-N6-cyclopentyladenosine significantly improved lung function and attenuated edema, cytokine expression, and myeloperoxidase levels compared with the vehicle-treated mice after ischemia-reperfusion. The incidence of lung ischemia-reperfusion injury was similar in the A(1) receptor knockout and wild-type mice; and 2-chloro-N6-cyclopentyladenosine had no effects in the A(1) receptor knockout mice. In vitro treatment of neutrophils with 2-chloro-N6-cyclopentyladenosine significantly reduced chemotaxis. CONCLUSIONS: Exogenous A(1) receptor activation improves lung function and decreases inflammation, edema, and neutrophil chemotaxis after ischemia and reperfusion. These results suggest a potential therapeutic application for A(1) receptor agonists for the prevention of lung ischemia-reperfusion injury after transplantation.
    The Journal of thoracic and cardiovascular surgery 02/2013; 145(6). DOI:10.1016/j.jtcvs.2013.01.006 · 3.99 Impact Factor

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