Biliverdin Protects the Isolated Rat Lungs from Ischemia-reperfusion Injury via Antioxidative, Anti-inflammatory and Anti-apoptotic Effects

Tian, Wen‐de; Weng, Ping; Sheng, Qiong; Chen, Junliang; Zhang, Peng; Zhang, Jiru; Du, Bin; Wu, Min-Chen; Pang, Qingfeng; Chu, Jianjun

doi:10.4103/0366-6999.202735

Cited by 15 publications

(11 citation statements)

References 27 publications

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“…Here, we found that IR significantly induced both apoptotic and necrotic cell death in the lung tissue. Caspase-dependent apoptosis is considered as a classical contributor to IR-induced lung injury, and the effectiveness of antiapoptotic therapies has been well demonstrated in previous studies [ 5 , 6 , 20 , 21 ]. In this study, z-VAD-fmk, a pan caspase inhibitor, significantly reduced apoptotic cell death and pathological severity in the lung tissue and decreased inflammatory markers and protein levels in BAL fluid as well.…”

Section: Discussionmentioning

confidence: 99%

“…Necroptosis shares similar morphologic features with necrosis, and accumulating evidences have highlighted its importance in mediating various pathophysiologic events [ 12 , 24 – 29 ]. Mixed lineage kinase domain-like protein (MLKL) is identified as a key component downstream of RIP3 in the execution of RIP1-mediated necroptosis, and MLKL trimerization and translocation facilitate the channel formation on the plasma membrane through which DAMPs are released [ 21 , 30 , 31 ]. Thus, necroptosis is typically characterized by cellular swelling and rupture, and the loss of cellular membrane integrity would promote inflammation via the release of DAMPs into the extracellular environment [ 22 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

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Necrostatin-1 Synergizes the Pan Caspase Inhibitor to Attenuate Lung Injury Induced by Ischemia Reperfusion in Rats

Wang

Chen

Xiong

et al. 2020

Mediators of Inflammation

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Background. Both apoptosis and necroptosis have been recognized to be involved in ischemia reperfusion-induced lung injury. We aimed to compare the efficacies of therapies targeting necroptosis and apoptosis and to determine if there is a synergistic effect between the two therapies in reducing lung ischemia reperfusion injury. Methods. Forty Sprague-Dawley rats were randomized into 5 groups: sham (SM) group, ischemia reperfusion (IR) group, necrostatin-1+ischemia reperfusion (NI) group, carbobenzoxy-Val-Ala-Asp-fluoromethylketone+ischemia reperfusion (ZI) group, and necrostatin-1+carbobenzoxy-Val-Ala-Asp-fluoromethylketone+ischemia reperfusion (NZ) group. The left lung hilum was exposed without being clamped in rats from the SM group, whereas the rats were subjected to lung ischemia reperfusion by clamping the left lung hilum for 1 hour, followed by reperfusion for 3 hours in the IR group. 1 mg/kg necrostatin-1 (Nec-1: a specific necroptosis inhibitor) and 3 mg/kg carbobenzoxy-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk: a pan caspase inhibitor) were intraperitoneally administrated prior to ischemia in NI and ZI groups, respectively, and the rats received combined administration of Nec-1 and z-VAD-fmk in the NZ group. Upon reperfusion, expressions of receptor-interacting protein 1 (RIP1), receptor-interacting protein 3 (RIP3), and caspase-8 were measured, and the flow cytometry analysis was used to assess the cell death patterns in the lung tissue. Moreover, inflammatory marker levels in the bronchoalveolar lavage fluid and pulmonary edema were evaluated. Results. Both Nec-1 and z-VAD-fmk, either alone or in combination, significantly reduced morphological damage, inflammatory markers, and edema in lung tissues following reperfusion, and cotreatment of z-VAD-fmk with Nec-1 produced the optimal effect. The rats treated with Nec-1 had lower levels of inflammatory markers in the bronchoalveolar lavage fluid than those receiving z-VAD-fmk alone ( P < 0.05 ). Interestingly, the z-VAD-fmk administration upregulated RIP1 and RIP3 expressions in the lung tissue from the ZI group compared to those in the IR group ( P < 0.05 ). Reperfusion significantly increased the percentages of necrotic and apoptotic cells in lung tissue single-cell suspension, which could be decreased by Nec-1 and z-VAD-fmk, respectively ( P < 0.05 ). Conclusions. Nec-1 synergizes the pan caspase inhibitor to attenuate lung ischemia reperfusion injury in rats. Our data support the potential use of Nec-1 in lung transplantation-related disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Necrostatin-1 Synergizes the Pan Caspase Inhibitor to Attenuate Lung Injury Induced by Ischemia Reperfusion in Rats

Wang

Chen

Xiong

et al. 2020

Mediators of Inflammation

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“…A variety of studies have shown that, in the development and manifestations of ALI, apoptosis is thought to be closely related to the severity of ALI [58,59]. For example, extensive apoptosis of pulmonary alveolar type II epithelial cells has been shown to be responsible for the impairment of the epithelial barrier function and the remodeling of certain mesenchymal cells in ALI [60].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inﬂammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway

et al. 2018

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Acute lung injury (ALI) is a critical clinical condition with a high mortality rate, characterized with excessive uncontrolled inflammation and apoptosis. Recently, microRNAs (miRNAs) have been found to play crucial roles in the amelioration of various inflammation-induced diseases, including ALI. However, it remains unknown the biological function and regulatory mechanisms of miRNAs in the regulation of inﬂammation and apoptosis in ALI. The aim of this study is to identify and evaluate the potential role of miRNAs in ALI and reveal the underlying molecular mechanisms of their effects. Here, we analyzed microRNA expression profiles in lung tissues from LPS-challenged mice using miRNA microarray. Because microRNA-27a (miR-27a) was one of the miRNAs being most significantly downregulated, which has an important role in regulation of inflammation, we investigated its function. Overexpression of miR-27a by agomir-27a improved lung injury, as evidenced by the reduced histopathological changes, lung wet/dry (W/D) ratio, lung microvascular permeability and apoptosis in the lung tissues, as well as ameliorative survival of ALI mice. This was accompanied by the alleviating of inflammation, such as the reduced total BALF cell and neutrophil counts, decreased levels of tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-6) interleukin-1β (IL-1β) and myeloperoxidase (MPO) activity in BAL fluid. Toll-like receptor 4 (TLR4), an important regulator of the nuclear factor kappa-B (NF-κB) signaling pathway, was identified as a novel target of miR-27a in RAW264.7 cells. Furthermore, our results showed that LPS stimulation increased the expression of MyD88 and NF-κB p65 (p-p65), but inhibited the expression of inhibitor of nuclear factor-κB-α (IκB-α), suggesting the activation of NF-κB signaling pathway. Further investigations revealed that agomir-miR-27a reversed the promoting effect of LPS on NF-κB signaling pathway. The results here suggested that miR-27a alleviates LPS-induced ALI in mice via reducing inﬂammation and apoptosis through blocking TLR4/MyD88/NF-κB activation.

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“…Haptoglobin may also interface with other anti-inflammatory pathways, as it stimulates the expression of heme oxygenase (Belcher et al, 2018), the enzyme responsible for converting heme from its pro-oxidant form to a molecule called biliverdin (Medzhitov et al, 2012;McDonagh, 2001). Biliverdin has anti-inflammatory (Tian et al, 2017) and anti-viral (Zhu et al, 2010) properties, and also has putative antioxidant properties (Baylor and Butler, 2019;Mancuso et al, 2012). Thus, inflammation may simultaneously result in an increase in oxidative damage, while also promoting the production of molecules and enzymes associated with anti-inflammatory and antioxidant functions.…”

Section: Introductionmentioning

confidence: 99%

Low-dose immune challenges result in detectable levels of oxidative damage

Armour

Bruner

Hines

et al. 2020

Journal of Experimental Biology

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Infection can result in substantial costs to animals, so they frequently respond by removing infectious agents with an immune response. However, immune responses entail their own costs, including upregulation of processes that destroy pathogens (e.g. the production of reactive oxygen species) and processes that limit the extent of self-damage during the immune response (e.g. production of anti-inflammatory proteins such as haptoglobin). Here, we simulated bacterial infection across a 1000-fold range using lipopolysaccharide (LPS) administered to northern bobwhite quail (Colinus virginianus), and quantified metrics related to pro-inflammatory conditions [i.e. generation of oxidative damage (d-ROMs), depletion of antioxidant capacity], anti-inflammatory mechanisms (i.e. production of haptoglobin, expression of the enzyme heme oxygenase, production of the organic molecule biliverdin) and nutritional physiology (e.g. circulating triglyceride levels, maintenance of body mass). We detected increases in levels of haptoglobin and d-ROMs even at LPS doses that are 1/1000th the concentration of doses frequently used in ecoimmunological studies, while loss of body mass and decreases in circulating triglycerides manifested only in individuals receiving the highest dose of LPS (1 mg LPS kg −1 body mass), highlighting variation among dosedependent responses. Additionally, individuals that lost body mass during the course of the experiment had lower levels of circulating triglycerides, and those with more oxidative damage had greater levels of heme oxygenase expression, which highlights the complex interplay between pro-and anti-inflammatory processes. Because low doses of LPS may simulate natural infection levels, variation in dose-dependent physiological responses may be particularly important in modeling how free-living animals navigate immune challenges.

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Biliverdin Protects the Isolated Rat Lungs from Ischemia-reperfusion Injury via Antioxidative, Anti-inflammatory and Anti-apoptotic Effects

Cited by 15 publications

References 27 publications

Necrostatin-1 Synergizes the Pan Caspase Inhibitor to Attenuate Lung Injury Induced by Ischemia Reperfusion in Rats

Necrostatin-1 Synergizes the Pan Caspase Inhibitor to Attenuate Lung Injury Induced by Ischemia Reperfusion in Rats

MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inﬂammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway

Low-dose immune challenges result in detectable levels of oxidative damage

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