Protective Effects of Neural Crest-Derived Stem Cell-Conditioned Media against Ischemia-Reperfusion-Induced Lung Injury in Rats

Because both the biosynthesis of nitric oxide (NO.) and its metabolic fate are related to molecular O2, we hypothesized that hypoxia would alter the effects of NO. during ischemia-reperfusion (IR) in the lung. In this study, buffer-perfused lungs from rabbits underwent either normoxic IR (AI), in which lungs were ventilated with 21% O2 during ischemia and reperfusion, or hypoxic IR (NI), in which lungs were ventilated with 95% N2 during ischemia followed by reoxygenation with 21% O2. Lung weight gain (WG) and pulmonary artery pressure (Ppa) were monitored continuously, and microvascular pressure (Pmv) was measured after reperfusion to calculate pulmonary vascular resistance. We found that both AI and NI produced acute lung injury, as shown by increased WG and Ppa during reperfusion. In AI, where perfusate PO2 was > 100 mmHg, the administration of the NO. synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) before ischemia worsened WG and Ppa. Pmv also increased, suggesting a hydrostatic mechanism involved in edema formation. The effects of L-NAME could be attenuated by giving L-arginine and exogenous NO. donors before ischemia or before reperfusion. Partial protection was also provided by superoxide dismutase. In contrast, lung injury in NI at perfusate PO2 of 25-30 mmHg was attenuated by L-NAME; this effect could be reversed by L-arginine. Exogenous NO. donors given either before ischemia or before reperfusion, however, did not increase lung injury. NO. production was measured by quantifying the total nitrogen oxides (NOx) accumulating in the perfusate. The average rate of NOx accumulation was greater in AI than in NI. We conclude that hypoxia prevented the protective effects of NO on AI lung injury. The effects of hypoxia may be related to lower NO. production relative to oxidant stress during IR and/or altered metabolic fates of NO.-mediated production of peroxynitrite by hypoxic ischemia.

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Mesenchymal Stromal (stem) Cell (MSC) therapy modulates miR-193b-5p expression to attenuate sepsis-induced acute lung injury

European Respiratory Journal ◽

10.1183/13993003.04216-2020 ◽

2021 ◽

pp. 2004216

Author(s):

Claudia C. dos Santos ◽

Hajera Amatullah ◽

Chirag M. Vaswani ◽

Tatiana Maron-Gutierrez ◽

Michael Kim ◽

...

Keyword(s):

Stem Cell ◽

Lung Injury ◽

Conditioned Media ◽

Therapeutic Effects ◽

Host Immune System ◽

Gene And Protein Expression ◽

Stromal Stem Cell ◽

Mesenchymal Stromal Stem Cell ◽

Deficient Mice

Although mesenchymal stromal (stem) cell (MSC) administration attenuates sepsis-induced lung injury in pre-clinical models, the mechanism(s) of action and host immune system contributions to its therapeutic effects, remain elusive. We show that treatment with MSCs decreased expression of host-derived microRNA (miR)-193b-5p and increased expression of its target gene, the tight junctional protein occludin (Ocln), in lungs from septic mice. Mutating the Ocln 3′ UTR miR-193b-5p binding sequence impaired binding to Ocln mRNA. Inhibition of miR-193b-5p in human primary pulmonary microvascular endothelial cells (HPMECs) prevents tumor necrosis factor (TNF)-induced decrease in Ocln gene and protein expression and loss of barrier function. MSC conditioned media mitigated TNF-induced miR-193b-5p upregulation and Ocln downregulation in vitro. When administered in vivo, MSC conditioned media recapitulated the effects of MSC administration on pulmonary miR-193b-5p and Ocln expression. MiR-193b deficient mice were resistant to pulmonary inflammation and injury induced by LPS instillation. Silencing of Ocln in miR-193b deficient mice partially recovered the susceptibility to LPS-induced lung injury. In vivo inhibition of miR-193b-5p protected mice from endotoxin-induced lung injury. Finally, the clinical significance of these results was supported by the finding of increased miR-193b-5p expression levels in lung autopsy samples from Acute Respiratory Distress Syndrome patients who died with diffuse alveolar damage.

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Therapeutic Applications of Carbon Monoxide

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/360815 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 20

Author(s):

Melissa Knauert ◽

Sandeep Vangala ◽

Maria Haslip ◽

Patty J. Lee

Keyword(s):

Carbon Monoxide ◽

Lung Injury ◽

Ischemia Reperfusion ◽

Heme Oxygenase 1 ◽

Protective Effects ◽

Phase Ii Trials ◽

Therapeutic Implications ◽

Damage Models ◽

Therapeutic Benefits ◽

Stress States

Heme oxygenase-1 (HO-1) is a regulated enzyme induced in multiple stress states. Carbon monoxide (CO) is a product of HO catalysis of heme. In many circumstances, CO appears to functionally replace HO-1, and CO is known to have endogenous anti-inflammatory, anti-apoptotic, and antiproliferative effects. CO is well studied in anoxia-reoxygenation and ischemia-reperfusion models and has advanced to phase II trials for treatment of several clinical entities. In alternative injury models, laboratories have used sepsis, acute lung injury, and systemic inflammatory challenges to assess the ability of CO to rescue cells, organs, and organisms. Hopefully, the research supporting the protective effects of CO in animal models will translate into therapeutic benefits for patients. Preclinical studies of CO are now moving towards more complex damage models that reflect polymicrobial sepsis or two-step injuries, such as sepsis complicated by acute respiratory distress syndrome. Furthermore, co-treatment and post-treatment with CO are being explored in which the insult occurs before there is an opportunity to intervene therapeutically. The aim of this review is to discuss the potential therapeutic implications of CO with a focus on lung injury and sepsis-related models.

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The protective effects of paricalcitol on renal ischemia reperfusion induced lung injury

10.1183/13993003.congress-2018.pa4297 ◽

2018 ◽

Author(s):

Süreyya Yilmaz ◽

Zülfükar Yilmaz ◽

Ali Kemal Kadiroğlu ◽

Veysi Bahadır ◽

İbrahim Kaplan ◽

...

Keyword(s):

Lung Injury ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Protective Effects

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Protective effects of hyperbaric oxygen and iloprost on ischemia/reperfusion-induced lung injury in a rabbit model

European Journal of Medical Research ◽

10.1186/2047-783x-17-14 ◽

2012 ◽

Vol 17 (1) ◽

Cited By ~ 12

Author(s):

Ş Bozok ◽

G Ilhan ◽

Y Yilmaz ◽

Z Dökümcü ◽

L Tumkaya ◽

...

Keyword(s):

Lung Injury ◽

Hyperbaric Oxygen ◽

Ischemia Reperfusion ◽

Rabbit Model ◽

Protective Effects

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PECAM-directed delivery of catalase to endothelium protects against pulmonary vascular oxidative stress

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00021.2003 ◽

2003 ◽

Vol 285 (2) ◽

pp. L283-L292 ◽

Cited By ~ 61

Author(s):

Melpo Christofidou-Solomidou ◽

Arnaud Scherpereel ◽

Rainer Wiewrodt ◽

Kimmie Ng ◽

Thomas Sweitzer ◽

...

Keyword(s):

Oxidative Stress ◽

Lung Injury ◽

Intravenous Injection ◽

Targeted Delivery ◽

Ischemia Reperfusion ◽

Therapeutic Interventions ◽

Protective Effects ◽

Stress Injury ◽

Pulmonary Endothelium

Targeted delivery of drugs to vascular endothelium promises more effective and specific therapies in many disease conditions, including acute lung injury (ALI). This study evaluates the therapeutic effect of drug targeting to PECAM (platelet/endothelial cell adhesion molecule-1) in vivo in the context of pulmonary oxidative stress. Endothelial injury by reactive oxygen species (e.g., H2O2) is involved in many disease conditions, including ALI/acute respiratory distress syndrome and ischemia-reperfusion. To optimize delivery of antioxidant therapeutics, we conjugated catalase with PECAM antibodies and tested properties of anti-PECAM/catalase conjugates in cell culture and mice. Anti-PECAM/catalase, but not an IgG/catalase counterpart, bound specifically to PECAM-expressing cells, augmented their H2O2-degrading capacity, and protected them against H2O2 toxicity. Anti-PECAM/catalase, but not IgG/catalase, rapidly accumulated in the lungs after intravenous injection in mice, where it was confined to the pulmonary endothelium. To test its protective effect, we employed a murine model of oxidative lung injury induced by glucose oxidase coupled with thrombomodulin antibody (anti-TM/GOX). After intravenous injection in mice, anti-TM/GOX binds to pulmonary endothelium and produces H2O2, which causes lung injury and 100% lethality within 7 h. Coinjection of anti-PECAM/catalase protected against anti-TM/GOX-induced pulmonary oxidative stress, injury, and lethality, whereas polyethylene glycol catalase or IgG/catalase conjugates afforded only marginal protective effects. This result validates vascular immunotargeting as a prospective strategy for therapeutic interventions aimed at immediate protective effects, e.g., for augmentation of antioxidant defense in the pulmonary endothelium and treatment of ALI.

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Protective Effects of Keratinocyte Growth Factor-2 on Ischemia–Reperfusion–Induced Lung Injury in Rats

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2013-0268oc ◽

2014 ◽

Vol 50 (6) ◽

pp. 1156-1165 ◽

Cited By ~ 18

Author(s):

Xiaocong Fang ◽

Lingyan Wang ◽

Lin Shi ◽

Chengshui Chen ◽

Qun Wang ◽

...

Keyword(s):

Growth Factor ◽

Lung Injury ◽

Ischemia Reperfusion ◽

Keratinocyte Growth Factor ◽

Protective Effects

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Mitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00278.2010 ◽

2011 ◽

Vol 300 (3) ◽

pp. L362-L369 ◽

Cited By ~ 39

Author(s):

Amit K. Yadav ◽

Stephen F. Doran ◽

Andrey A. Samal ◽

Ruchita Sharma ◽

Kokilavani Vedagiri ◽

...

Keyword(s):

Lung Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Weight Ratio ◽

Dry Weight ◽

Airway Epithelial Cells ◽

Normal Lung ◽

Protective Effects ◽

Quantitative Morphology ◽

Upper Airways

Nitrite (NO2−) has been shown to limit injury to the heart, liver, and kidneys in various models of ischemia-reperfusion injury. Potential protective effects of systemic NO2− in limiting lung injury or enhancing repair have not been documented. We assessed the efficacy and mechanisms by which postexposure intraperitoneal injections of NO2− mitigate chlorine (Cl2)-induced lung injury in rats. Rats were exposed to Cl2 (400 ppm) for 30 min and returned to room air. NO2− (1 mg/kg) or saline was administered intraperitoneally at 10 min and 2, 4, and 6 h after exposure. Rats were killed at 6 or 24 h. Injury to airway and alveolar epithelia was assessed by quantitative morphology, protein concentrations, number of cells in bronchoalveolar lavage (BAL), and wet-to-dry lung weight ratio. Lipid peroxidation was assessed by measurement of lung F2-isoprostanes. Rats developed severe, but transient, hypoxemia. A significant increase of protein concentration, neutrophil numbers, airway epithelia in the BAL, and lung wet-to-dry weight ratio was evident at 6 h after Cl2 exposure. Quantitative morphology revealed extensive lung injury in the upper airways. Airway epithelial cells stained positive for terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL), but not caspase-3. Administration of NO2− resulted in lower BAL protein levels, significant reduction in the intensity of the TUNEL-positive cells, and normal lung wet-to-dry weight ratios. F2-isoprostane levels increased at 6 and 24 h after Cl2 exposure in NO2−- and saline-injected rats. This is the first demonstration that systemic NO2− administration mitigates airway and epithelial injury.

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