Abstract
Lung ischemia reperfusion (IR) is known to occur after lung transplantation or cardiac bypass. IR leads to tissue inflammation and damage and is also associated with increased morbidity and mortality. Various receptors are known to partake in activation of the innate immune system, but the downstream mechanism of tissue damage and inflammation is yet unknown. MicroRNAs (miRNAs) are in the forefront in regulating ischemia reperfusion injury and are involved in inflammatory response. Here, we have identified by high-throughput approach and evaluated a distinct set of miRNAs that may play a role in response to IR in rat lung tissue. The top three differentially expressed miRNAs were validated through quantitative PCRs in the IR rat lung model and an in vitro model of IR of hypoxia and reoxygenation exposed type II alveolar cells. Among the miRNAs, miR-18a-5p showed consistent downregulation in both the model systems on IR. Cellular and molecular analysis brought to light a crucial role of this miRNA in ischemia reperfusion. miR-18a-5p plays a role in IR-mediated apoptosis and ROS production and regulates the expression of neuropeptide Galanin. It also influences the nuclear localization of transcription factor: nuclear factor-erythroid 2-related factor (Nrf2) which in turn may regulate the expression of the miR-18a gene. Thus, we have not only established a rat model for lung IR and enumerated the important miRNAs involved in IR but have also extensively characterized the role of miR-18a-5p. This study will have important clinical and therapeutic implications for and during transplantation procedures.
Highlights
Patients with end-stage lung diseases or pulmonary disorders receive lung transplantation as a standard mode of treatment modality
We enumerate the microRNAs that are differentially expressed on rat lung ischemic reperfusion injury as compared to untreated rat lung tissue
We discovered that miR-18a-5p targets the neuropeptide Galanin mRNA and suppresses its translation
Summary
Patients with end-stage lung diseases or pulmonary disorders receive lung transplantation as a standard mode of treatment modality. Even though well established, has a low success rate compared to other solid organ transplants as it poses challenges in terms of survival of donor transplant in the recipient body [1]. This is mostly due to a clinical condition called primary graft dysfunction (PGD), which results from mild or acute lung injury posttransplantation [2]. Cessation of blood supply while excising the lungs from the donor for transplantation leads to ischemia and subsequent reperfusion during transplantation to the recipient This causes a rapid host inflammatory response leading to injury and possible dysfunction of the transplanted organ [5]. The extent of damage to the transplanted lung due to Oxidative Medicine and Cellular Longevity ischemia reperfusion determines the survival rate and functionality of the lung in the recipient body
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