scholarly journals Deficiency of cationic amino acid transporter-2 protects mice from hyperoxia-induced lung injury

2019 ◽  
Vol 316 (4) ◽  
pp. L598-L607 ◽  
Author(s):  
Yi Jin ◽  
Yusen Liu ◽  
Leif D. Nelin
Keyword(s):  
Nitric Oxide ◽  
Acute Lung Injury ◽  
Amino Acid ◽  
Lung Injury ◽  
Weight Ratio ◽  
No Production ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Cationic Amino Acid ◽  
Significant Difference

The pathology of acute lung injury (ALI) involves inducible nitric oxide (NO) synthase (iNOS)-derived NO-induced apoptosis of pulmonary endothelial cells. In vitro, iNOS-derived NO production has been shown to depend on the uptake of l-arginine by the cationic amino acid transporters (CAT). To test the hypothesis that mice deficient in CAT-2 ( slc7a2−/− on a C57BL/6 background) would be protected from hyperoxia-induced ALI, mice ( slc7a2−/− or wild-type) were placed in >95% oxygen (hyperoxia) or 21% oxygen (control) for 60 h. In wild-type mice exposed to hyperoxia, the exhaled nitric oxide (exNO) was twofold greater than in wild-type mice exposed to normoxia ( P < 0.005), whereas in slc7a2−/− mice there was no significant difference between exNO in animals exposed to hyperoxia or normoxia ( P = 0.95). Hyperoxia-exposed wild-type mice had greater ( P < 0.05) lung resistance and a lower ( P < 0.05) lung compliance than did hyperoxia-exposed slc7a2−/− mice. The lung wet-to-dry weight ratio was greater ( P < 0.005) in the hyperoxia-exposed wild-type mice than in hyperoxia-exposed slc7a2−/− mice. Neutrophil infiltration was lower ( P < 0.05) in the hyperoxia-exposed slc7a2−/− mice than in the hyperoxia-exposed wild-type mice as measured by myeloperoxidase activity. The protein concentration in bronchoalveolar lavage fluid was lower ( P < 0.001) in the hyperoxia-exposed slc7a2−/− mice than in similarly exposed wild-type mice. The percent of TUNEL-positive cells in the lung following hyperoxia exposure was significantly lower ( P < 0.001) in the slc7a2−/− mice than in the wild-type mice. These results are consistent with our hypothesis that lack of CAT-2 protects mice from acute lung injury.

scholarly journals Protective effect of Cordyceps sinensis extract on lipopolysaccharide-induced acute lung injury in mice

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Shuiqiao Fu ◽  
Weina Lu ◽  
Wenqiao Yu ◽  
Jun Hu
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protective Effect ◽  
Weight Ratio ◽  
Cordyceps Sinensis ◽  
Myeloperoxidase Activity ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Tnf Α ◽  
Cox 2

Abstract Background: To study the protective effect of Cordyceps sinensis extract (Dong Chong Xia Cao in Chinese [DCXC]) on experimental acute lung injury (ALI) mice. Methods and results: ALI model was induced by intratracheal-instilled lipopolysaccharide (LPS, 2.4 mg/kg) in BALB/c male mice. The mice were administrated DCXC (ig, 10, 30, 60 mg/kg) in 4 and 8 h after receiving LPS. Histopathological section, wet/dry lung weight ratio and myeloperoxidase activity were detected. Bronchoalveolar lavage fluid (BALF) was collected for cell count, the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and nitric oxide (NO) in BALF was detected by ELISA, the protein and mRNA expression of nuclear factor-κB p65 (NF-κB p65), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in lung tissue was detected by Western blot and RT-PCR. The result showed that DCXC could reduce the degree of histopathological injury, wet/dry weight ratio (W/D ratio) and myeloperoxidase activity (P<0.05) with a dose-dependent manner. The increased number of total cells, neutrophils and macrophages in BALF were significantly inhibited by DCXC treatment (P<0.05). The increased levels of TNF-α, IL-1β, IL-6 and NO in BALF after LPS administration was significantly reduced by DCXC (P<0.05). In addition, the increased protein and mRNA levels of iNOS, COX-2 and NF-κB p65 DNA binding ability in LPS group were dose-dependently reduced by DCXC treatment (P<0.05). Conclusion: DCXC could play an anti-inflammatory and antioxidant effect on LPS-induced ALI through inhibiting NF-κB p65 phosphorylation, and the expression of COX-2 and iNOS in lung. The result showed that DCXC has a potential protective effect on the ALI.

scholarly journals Nitric oxide can acutely modulate its biosynthesis through a negative feedback mechanism on l-arginine transport in cardiac myocytes

2010 ◽  
Vol 299 (2) ◽  
pp. C230-C239 ◽  
Author(s):  
Jiaguo Zhou ◽  
David D. Kim ◽  
R. Daniel Peluffo
Keyword(s):  
Nitric Oxide ◽  
Amino Acid ◽  
Cardiac Myocytes ◽  
Amino Acid Transporters ◽  
No Production ◽  
Cardiac Muscle Cells ◽  
No Donor ◽  
Rat Cardiomyocytes ◽  
Cationic Amino Acid ◽  
Intervention Point

Nitric oxide (NO) plays a central role as a cellular signaling molecule in health and disease. In the heart, NO decreases the rate of spontaneous beating and the velocity and extent of shortening and accelerates the velocity of relengthening. Since the cationic amino acid l-arginine (l-Arg) is the substrate for NO production by NO synthases (NOS), we tested whether the transporters that mediate l-Arg import in cardiac muscle cells represent an intervention point in the regulation of NO synthesis. Electrical currents activated by l-Arg with low apparent affinity in whole cell voltage-clamped rat cardiomyocytes were found to be rapidly and reversibly inhibited by NO donors. Radiotracer uptake studies performed on cardiac sarcolemmal vesicles revealed the presence of high-affinity/low-capacity and low-affinity/high-capacity components of cationic amino acid transport that were inhibited by the NO donor S-nitroso- N-acetyl-dl-penicillamine. NO inhibited uptake in a noncompetitive manner with Ki values of 275 and 827 nM for the high- and low-affinity component, respectively. Fluorescence spectroscopy experiments showed that millimolar concentrations of l-Arg initially promoted and then inhibited the release of endogenous NO in cardiomyocytes. Likewise, l-Arg currents measured in cardiac myocytes voltage clamped in the presence of 460 nM free intracellular Ca2+, a condition in which a Ca-CaM complex should activate endogenous NO production, showed fast activation followed by inhibition of l-Arg transport. The NOS inhibitor N-nitro-l-arginine methyl ester, but not blockers of downstream reactions, specifically removed this inhibitory component. These results demonstrate that NO acutely regulates its own biosynthesis by modulating the availability of l-Arg via cationic amino acid transporters.

scholarly journals Ganoderic acid A attenuates lipopolysaccharide-induced lung injury in mice

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Bing Wan ◽  
Yan Li ◽  
Shuangshuang Sun ◽  
Yang Yang ◽  
Yanling LV ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Weight Ratio ◽  
Dry Weight ◽  
Lavage Fluid ◽  
Myeloperoxidase Activity ◽  
Protective Effects ◽  
Ganoderic Acid ◽  
Lower Lung

Abstract The present study aimed to investigate the protective effects of ganoderic acid A (GAA) on lipopolysaccharide (LPS)-induced acute lung injury. In mouse model of LPS-induced acute lung injury, we found that GAA led to significantly lower lung wet-to-dry weight ratio and lung myeloperoxidase activity, and attenuated pathological damages. In addition, GAA increased superoxide dismutase activity, but decreased malondialdehyde content and proinflammatory cytokines levels in the bronchoalveolar lavage fluid. Mechanistically, GAA reduced the activation of Rho/ROCK/NF-κB pathway to inhibit LPS-induced inflammation. In conclusion, our study suggests that GAA attenuates acute lung injury in mouse model via the inhibition of Rho/ROCK/NF-κB pathway.

Exhalation of gaseous nitric oxide by rats in response to endotoxin and its absorption by the lungs

1997 ◽  
Vol 82 (1) ◽  
pp. 305-316 ◽  
Author(s):  
John T. Stitt ◽  
Arthur B. Dubois ◽  
James S. Douglas ◽  
Steven G. Shimada
Keyword(s):  
Nitric Oxide ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
No Synthase ◽  
No Production ◽  
Alveolar Air ◽  
Lipopolysaccharide Endotoxin ◽  
Early Biomarker ◽  
Dose Dependent ◽  
Expired Air

Stitt, John T., Arthur B. DuBois, James S. Douglas, and Steven G. Shimada. Exhalation of gaseous nitric oxide by rats in response to endotoxin and its absorption by the lungs. J. Appl. Physiol. 82(1): 305–316, 1997.—Rats injected with a lipopolysaccharide endotoxin produce detectable concentrations of nitric oxide gas (NO) in the expired air within 60 min. The concentration of NO reaches a plateau at 3 h. Production of the NO is dose dependent on lipopolysaccharide, and at a dose of 1 mg/kg iv, lipopolysaccharide alveolar concentrations of >260 parts per billion are observed. NO synthase inhibitors suppress this NO production in response to endotoxin. Experiments were conducted to ascertain the site of origin of this NO and to measure the capacity of the lungs to absorb NO from alveolar air. Results indicate that the endotoxin-induced NO originates from within the lungs themselves and that the lungs have the capacity to absorb >60% of NO that is presented to them. Lung tissues absorb ∼44–47% of the NO load, blood carries away between 15 and 19%, while the remainder is exhaled in the expired air. It is proposed that the exhalation of NO might prove useful as an early biomarker for acute lung injury.

Modulation of the l-arginine/nitric oxide signalling pathway in vascular endothelial cells

2004 ◽  
Vol 71 ◽  
pp. 143-156 ◽  
Author(s):  
Amanda W. Wyatt ◽  
Joern R. Steinert ◽  
Giovanni E. Mann
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Amino Acid ◽  
Protein Kinase ◽  
Signalling Pathway ◽  
No Production ◽  
Dependent Manner ◽  
Amino Acid Transport System ◽  
Membrane Hyperpolarization ◽  
Cationic Amino Acid

Nitric oxide (NO) is synthesized from l-arginine, and in endothelial cells influx of l-arginine is mediated predominantly via Na+-independent cationic amino acid transporters. Constitutive, Ca2+-calmodulin-sensitive eNOS (endothelial nitric oxide synthase) metabolizes l-arginine to NO and l-citrulline. eNOS is present in membrane caveolae and the cytosol and requires tetrahydrobiopterin, NADPH, FAD and FMN as additional cofactors for its activity. Supply of l-arginine for NO synthesis appears to be derived from a membrane-associated compartment distinct from the bulk intracellular amino acid pool, e.g. near invaginations of the plasma membrane referred to as 'lipid rafts' or caveolae. Co-localization of eNOS and the cationic amino acid transport system y+ in caveolae in part explains the 'arginine paradox', related to the phenomenon that in certain disease states eNOS requires an extracellular supply of l-arginine despite having sufficient intracellular l-arginine concentrations. Vasoactive agonists normally elevate [Ca2+]i (intracellular calcium concentration) in endothelial cells, thus stimulating NO production, whereas fluid shear stress, 17ϐ-oestradiol and insulin cause phosphorylation of the serine/threonine protein kinase Akt/protein kinase B in a phosphoinositide 3-kinase-dependent manner and activation of eNOS at basal [Ca2+]i levels. Adenosine causes an acute activation of p42/p44 mitogen-activated protein kinase and NO release, with membrane hyperpolarization leading to increased system y+ activity in fetal endothelial cells. In addition to acute stimulatory actions of D-glucose and insulin on l-arginine transport and NO synthesis, gestational diabetes, intrauterine growth retardation and pre-eclampsia induce phenotypic changes in the fetal vasculature, resulting in alterations in the l-arginine/NO signalling pathway and regulation of [Ca2+]i. These alterations may have significant implications for long-term programming of the fetal cardiovascular system.

Nitric oxide participates in early events associated with NNMU-induced acute lung injury in rats

1999 ◽  
Vol 276 (2) ◽  
pp. L263-L268 ◽  
Author(s):  
Wilhelm S. Cruz ◽  
John A. Corbett ◽  
William J. Longmore ◽  
Michael A. Moxley
Keyword(s):  
Nitric Oxide ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Ex Vivo ◽  
Neutrophil Infiltration ◽  
Inos Expression ◽  
Polymorphonuclear Neutrophil ◽  
No Production ◽  
Biochemical Mechanisms ◽  
Ex Vivo Culture

In this study, the biochemical mechanisms by which N-nitroso- N-methylurethane (NNMU) induces acute lung injury are examined. Polymorphonuclear neutrophil infiltration into the lungs first appears in the bronchoalveolar lavage (BAL) fluid 24 h after NNMU injection (10.58 ± 3.00% of total cells; P < 0.05 vs. control animals). However, NNMU-induced elevation of the alveolar-arterial O2 difference requires 72 h to develop. Daily intraperitoneal injections of the inducible nitric oxide (⋅ NO) synthase (iNOS)-selective inhibitor aminoguanidine (AG) initiated 24 h after NNMU administration improve the survival of NNMU-treated animals. However, AG administration initiated 48 or 72 h after NNMU injection does not significantly improve the survival of NNMU-treated animals. These results suggest that ⋅ NO participates in events that occur early in NNMU-induced acute lung injury. BAL cells isolated from rats 24 and 48 h after NNMU injection produce elevated ⋅ NO and express iNOS during a 24-h ex vivo culture. AG attenuates ⋅ NO production but does not affect iNOS expression, whereas actinomycin D prevents iNOS expression and attenuates ⋅ NO production by BAL cells during this ex vivo culture. These results suggest that NNMU-derived BAL cells can stimulate iNOS expression and ⋅ NO production during culture. In 48-h NNMU-exposed rats, iNOS expression is elevated in homogenates of whole lavaged lungs but not in BAL cells derived from the same lung. These findings suggest that the pathogenic mechanism by which NNMU induces acute lung injury involves BAL cell stimulation of iNOS expression and ⋅ NO production in lung tissue.

scholarly journals ADAM15 deficiency attenuates pulmonary hyperpermeability and acute lung injury in lipopolysaccharide-treated mice

2013 ◽  
Vol 304 (3) ◽  
pp. L135-L142 ◽  
Author(s):  
Chongxiu Sun ◽  
Richard S. Beard ◽  
Danielle L. McLean ◽  
Robert R. Rigor ◽  
Thomas Konia ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Weight Ratio ◽  
Dry Weight ◽  
Immunofluorescent Staining ◽  
Mouse Lung ◽  
Myeloperoxidase Activity ◽  
Barrier Dysfunction ◽  
Obvious Effect ◽  
Inflammatory Injury

ADAM15 is a disintegrin and metalloprotease recently implicated in cancer and chronic immune disorders. We have recently characterized ADAM15 as a mediator of endothelial barrier dysfunction. Whether this molecule contributes to acute inflammation has not been evaluated. The purpose of this study was to investigate the role of ADAM15 in mediating pulmonary microvascular leakage during acute inflammatory injury. Immunofluorescent staining and Western blotting revealed that the endothelium was the main source of ADAM15 in lung tissue. In a mouse model of acute lung injury induced by lipopolysaccharide (LPS), upregulation of ADAM15 was observed in association with pulmonary edema and neutrophil infiltration. The LPS-induced inflammatory injury, as demonstrated by bronchoalveolar lavage neutrophil count, lung wet-to-dry weight ratio, and myeloperoxidase activity, was significantly attenuated in Adam15 −/− mice. Studies with primary cell culture demonstrated abundant ADAM15 expression in endothelial cells (ECs) of mouse lung but not in neutrophils. Deficiency of ADAM15 in ECs had no obvious effect on basal permeability but significantly attenuated hyperpermeability response to LPS as evidenced by albumin flux assay and measurements of transendothelial electrical resistance, respectively. ADAM15 deficiency also reduced neutrophil chemotactic transmigration across endothelial barriers in the presence or absence of formyl-methionyl-leucyl-phenylalanine (fMLP). Rescue expression of ADAM15 in Adam15 −/− ECs restored neutrophil transendothelial migration. These data indicate that ADAM15 upregulation contributes to inflammatory lung injury by promoting endothelial hyperpermeability and neutrophil transmigration.

scholarly journals Agmatine Protects against Zymosan-Induced Acute Lung Injury in Mice by Inhibiting NF-κB-Mediated Inflammatory Response

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Xuanfei Li ◽  
Zheng Liu ◽  
He Jin ◽  
Xia Fan ◽  
Xue Yang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Inflammation ◽  
Weight Ratio ◽  
Dry Weight ◽  
Lavage Fluid ◽  
Myeloperoxidase Activity ◽  
Beneficial Effects ◽  
Hypoxic Ischemia ◽  
Tnf Α

Acute lung injury (ALI) is characterized by overwhelming lung inflammation and anti-inflammation treatment is proposed to be a therapeutic strategy for ALI. Agmatine, a cationic polyamine formed by decarboxylation of L-arginine, is an endogenous neuromodulator that plays protective roles in diverse central nervous system (CNS) disorders. Consistent with its neuromodulatory and neuroprotective properties, agmatine has been reported to have beneficial effects on depression, anxiety, hypoxic ischemia, Parkinson’s disease, and gastric disorder. In this study, we tested the effect of agmatine on the lung inflammation induced by Zymosan (ZYM) challenge in mice. We found that agmatine treatment relieved ZYM-induced acute lung injury, as evidenced by the reduced histological scores, wet/dry weight ratio, and myeloperoxidase activity in the lung tissue. This was accompanied by reduced levels of TNF-α, IL-1β, and IL-6 in lung and bronchoalveolar lavage fluid and decreased iNOS expression in lung. Furthermore, agmatine inhibited the phosphorylation and degradation of IκB and subsequently blocked the activation of nuclear factor (NF)-κB induced by Zymosan. Taken together, our results showed that agmatine treatment inhibited NF-κB signaling in lungs and protected mice against ALI induced by Zymosan, suggesting agmatine may be a potential safe and effective approach for the treatment of ALI.

scholarly journals Therapeutic Effect of C-Phycocyanin Extracted from Blue Green Algae in a Rat Model of Acute Lung Injury Induced by Lipopolysaccharide

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Pak-on Leung ◽  
Hao-Hsien Lee ◽  
Yu-Chien Kung ◽  
Ming-Fan Tsai ◽  
Tz-Chong Chou
Keyword(s):  
Body Weight ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Green Algae ◽  
Inflammatory Responses ◽  
Weight Ratio ◽  
Lung Edema ◽  
Polymorphonuclear Cells ◽  
Myeloperoxidase Activity ◽  
Blue Green Algae

C-Phycocyanin (CPC), extracted from blue green algae, is a dietary nutritional supplement due to its several beneficial pharmacological effects. This study was conducted to evaluate whether CPC protects against lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in rats. Rats were challenged with LPS (5 mg/kg body weight) intratracheally to induce ALI. After 3 h LPS instillation, rats were administrated with CPC (50 mg/kg body weight, i.p.) for another 3 h. Our results showed that posttreatment with CPC significantly inhibited LPS-induced elevation of protein concentration, nitrite/nitrate level, release of proinflammatory cytokines, the number of total polymorphonuclear cells in bronchoalveolar lavage fluid, and lung edema evidenced by decrease of lung wet/dry weight ratio accompanied by a remarkable improvement of lung histopathological alterations. Furthermore, CPC significantly attenuated LPS-induced myeloperoxidase activity,O2−formation, expression of inducible nitric oxide synthase, and cyclooxygenase-2 as well as nuclear factor-kappa B (NF-κB) activation in lungs. Additionally, CPC significantly downregulated proapoptotic proteins such as caspase-3 and Bax, but upregulated antiapoptotic proteins such as Bcl-2 and Bcl-XL in lungs exposed to LPS. These findings indicate that CPC could be potentially useful for treatment of LPS-related ALI by inhibiting inflammatory responses and apoptosis in lung tissues.

Viola yedoensis Liposoluble Fraction Ameliorates Lipopolysaccharide-Induced Acute Lung Injury in Mice

2012 ◽  
Vol 40 (05) ◽  
pp. 1007-1018 ◽  
Author(s):  
Wen Li ◽  
Jun-Yun Xie ◽  
Hong Li ◽  
Yun-Yi Zhang ◽  
Jie Cao ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Chemical Constituents ◽  
Chinese Herb ◽  
Weight Ratio ◽  
Acute Injury ◽  
Myeloperoxidase Activity ◽  
Proinflammatory Mediators

Viola yedoensis is a component of traditional Chinese herb medicine for inflammatory diseases. Chemical constituents of V. yedoensis have been shown to possess antibacterial, anti-HIV, and anticoagulant effects in experimental research; however, their anti-inflammatory properties remain to be demonstrated. In this study, a mouse model of lipopolysaccharide (LPS)-induced acute lung injury was used to investigate the effect of petroleum ether fraction of V. yedoensis (PEVY) on inflammation in vivo. After being shown to have anti-complementary activity in vitro, PEVY was orally administered to the mice at doses of 2, 4, and 8 mg/kg. Treatment with PEVY significantly decreased the wet-to-dry weight ratio of the lung, total cells, red blood cells, protein concentration, and myeloperoxidase activity in bronchoalveolar lavage fluid. PEVY markedly attenuated lung injury with improved lung morphology and reduced complement deposition. In addition, PEVY suppressed the expression of pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6. Taken together, PEVY protects the lung from acute injury, potentially via inhibiting the activation of the complement system and excessive production of proinflammatory mediators.

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