Fluid resuscitation therapy in endotoxemic hamsters improves survival and attenuates capillary perfusion deficits and inflammatory responses by a mechanism related to nitric oxide

Sepsis is characterized by increased microvascular permeability and regional variations in capillary perfusion, which may be modulated by nitric oxide (NO) and reversed by fluid resuscitation (FR). The effects of saline FR and NO synthase blockade [by NG-nitro-L-arginine methyl ester (L-NAME)] on microvascular albumin transport and perfused capillary density were assessed in anaesthetized Wistar rats with acute normodynamic endotoxaemia. Separate dual-isotope techniques were employed to measure the permeability index (PIA) and the permeability×surface area product index (PIB), which provide different and complementary information regarding blood–tissue albumin exchange. PIA represents the tissue/blood distribution volume ratio of albumin. PIB is a composite measure of endothelial permeability and the vascular surface area available for albumin exchange, and therefore takes into account the effect of altered blood volume. Capillary density was quantified by fluorescence microscopy following circulation of Evans Blue-labelled albumin. Compared with controls, PIA was reduced significantly in lipopolysaccharide (LPS)-treated animals in skeletal muscle and skin, probably due to blood volume redistribution rather than to changes in permeability. PIB was increased significantly in LPS-treated animals in the kidney, mesentery, skeletal muscle, skin and lung, and in the small bowel following FR. FR also improved the LPS-induced metabolic base deficit, but did not alter capillary density. L-NAME significantly attenuated the LPS-induced rise in PIB in the lung. In conclusion, acute endotoxaemia induces tissue-dependent variations in microvascular albumin exchange. FR improves acid–base disturbance in endotoxaemia, through mechanisms other than microvascular recruitment. NO appears to increase microvascular permeability in endotoxaemia, an effect that may be attenuated by L-NAME, particularly in the lung.

Download Full-text

Nitric oxide increases IL-8 gene transcription and mRNA stability to enhance IL-8 gene expression in lung epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00165.2004 ◽

2004 ◽

Vol 287 (4) ◽

pp. L764-L773 ◽

Cited By ~ 34

Author(s):

Loretta Sparkman ◽

Vijayakumar Boggaram

Keyword(s):

Gene Expression ◽

Nitric Oxide ◽

Protein Kinase ◽

Epithelial Cells ◽

Gene Transcription ◽

Mrna Stability ◽

Inflammatory Responses ◽

Lung Epithelial Cells ◽

Mrna Levels ◽

Lung Epithelial

Interleukin (IL)-8, a C-X-C chemokine, is a potent chemoattractant and an activator for neutrophils, T cells, and other immune cells. The airway and respiratory epithelia play important roles in the initiation and modulation of inflammatory responses via production of cytokines and surfactant. The association between elevated levels of nitric oxide (NO) and IL-8 in acute lung injury associated with sepsis, acute respiratory distress syndrome, respiratory syncytial virus infection in infants, and other inflammatory diseases suggested that NO may play important roles in the control of IL-8 gene expression in the lung. We investigated the role of NO in the control of IL-8 gene expression in H441 lung epithelial cells. We found that a variety of NO donors significantly induced IL-8 mRNA levels, and the increase in IL-8 mRNA was associated with an increase in IL-8 protein. NO induction of IL-8 mRNA was due to increases in IL-8 gene transcription and mRNA stability. NO induction of IL-8 mRNA levels was not inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and KT-5823, inhibitors of soluble guanylate cyclase and protein kinase G, respectively, and 8-bromo-cGMP did not increase IL-8 mRNA levels. This indicated that NO induces IL-8 mRNA levels independently of changes in the intracellular cGMP levels. NO induction of IL-8 mRNA was significantly reduced by inhibitors of extracellular regulated kinase and protein kinase C. IL-8 induction by NO was also reduced by hydroxyl radical scavengers such as dimethyl sulfoxide and dimethylthiourea, indicating the involvement of hydroxyl radicals in the induction process. NO induction of IL-8 gene expression could be a significant contributing factor in the initiation and induction of inflammatory response in the respiratory epithelium.

Download Full-text

Inhaled nitric oxide reduces lung edema during fluid resuscitation in ovine acute lung injury

Intensive Care Medicine ◽

10.1007/s00134-003-1790-3 ◽

2003 ◽

Vol 29 (10) ◽

pp. 1790-1797 ◽

Cited By ~ 3

Author(s):

Henning D. Stubbe ◽

Martin Westphal ◽

Hugo Van Aken ◽

Christoph Hucklenbruch ◽

Stefan Lauer ◽

...

Keyword(s):

Nitric Oxide ◽

Acute Lung Injury ◽

Lung Injury ◽

Fluid Resuscitation ◽

Inhaled Nitric Oxide ◽

Lung Edema

Download Full-text

A Hypothesis: Hydrogen Sulfide Might Be Neuroprotective against Subarachnoid Hemorrhage Induced Brain Injury

The Scientific World JOURNAL ◽

10.1155/2014/432318 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 14

Author(s):

Yong-Peng Yu ◽

Xiang-Lin Chi ◽

Li-Jun Liu

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Hydrogen Sulfide ◽

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Inflammatory Responses ◽

Ischemia Reperfusion Injury ◽

Leukocyte Adhesion ◽

Ischemia Reperfusion ◽

The Brain

Gases such as nitric oxide (NO) and carbon monoxide (CO) play important roles both in normal physiology and in disease. Recent studies have shown that hydrogen sulfide (H2S) protects neurons against oxidative stress and ischemia-reperfusion injury and attenuates lipopolysaccharides (LPS) induced neuroinflammation in microglia, exhibiting anti-inflammatory and antiapoptotic activities. The gas H2S is emerging as a novel regulator of important physiologic functions such as arterial diameter, blood flow, and leukocyte adhesion. It has been known that multiple factors, including oxidative stress, free radicals, and neuronal nitric oxide synthesis as well as abnormal inflammatory responses, are involved in the mechanism underlying the brain injury after subarachnoid hemorrhage (SAH). Based on the multiple physiologic functions of H2S, we speculate that it might be a promising, effective, and specific therapy for brain injury after SAH.

Download Full-text

Disruption of renal peritubular blood flow in lipopolysaccharide-induced renal failure: role of nitric oxide and caspases

AJP Renal Physiology ◽

10.1152/ajprenal.00124.2005 ◽

2005 ◽

Vol 289 (6) ◽

pp. F1324-F1332 ◽

Cited By ~ 82

Author(s):

Manish M. Tiwari ◽

Robert W. Brock ◽

Judit K. Megyesi ◽

Gur P. Kaushal ◽

Philip R. Mayeux

Keyword(s):

Nitric Oxide ◽

Renal Failure ◽

Blood Flow ◽

Saline Group ◽

No Production ◽

Capillary Perfusion ◽

Peritubular Capillary ◽

Synthase Inhibitor ◽

Peritubular Capillary Perfusion

Acute renal failure (ARF) is a frequent and serious complication of endotoxemia caused by lipopolysaccharide (LPS) and contributes significantly to mortality. The present studies were undertaken to examine the roles of nitric oxide (NO) and caspase activation on renal peritubular blood flow and apoptosis in a murine model of LPS-induced ARF. Male C57BL/6 mice treated with LPS ( Escherichia coli) at a dose of 10 mg/kg developed ARF at 18 h. Renal failure was associated with a significant decrease in peritubular capillary perfusion. Vessels with no flow increased from 7 ± 3% in the saline group to 30 ± 4% in the LPS group ( P < 0.01). Both the inducible NO synthase inhibitor l- N6-1-iminoethyl-lysine (l-NIL) and the nonselective caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (Z-VAD) prevented renal failure and reversed perfusion deficits. Renal failure was also associated with an increase in renal caspase-3 activity and an increase in renal apoptosis. Both l-NIL and Z-VAD prevented these changes. LPS caused an increase in NO production that was blocked by l-NIL but not by Z-VAD. Taken together, these data suggest NO-mediated activation of renal caspases and the resulting disruption in peritubular blood flow are an important mechanism of LPS-induced ARF.

Download Full-text

Toxoplasma gondii Cyclophilin 18-Mediated Production of Nitric Oxide Induces Bradyzoite Conversion in a CCR5-Dependent Manner

Infection and Immunity ◽

10.1128/iai.00361-09 ◽

2009 ◽

Vol 77 (9) ◽

pp. 3686-3695 ◽

Cited By ~ 30

Author(s):

Hany M. Ibrahim ◽

Hiroshi Bannai ◽

Xuenan Xuan ◽

Yoshifumi Nishikawa

Keyword(s):

Nitric Oxide ◽

Toxoplasma Gondii ◽

Inflammatory Responses ◽

Interleukin 12 ◽

Dependent Manner ◽

Independent Manner ◽

Necrosis Factor Alpha ◽

Parasite Multiplication ◽

Factor Alpha

ABSTRACT Toxoplasma gondii modulates pro- and anti-inflammatory responses to regulate parasite multiplication and host survival. Pressure from the immune response causes the conversion of tachyzoites into slowly dividing bradyzoites. The regulatory mechanisms involved in this switch are poorly understood. The aim of this study was to investigate the immunomodulatory role of T. gondii cyclophilin 18 (TgCyp18) in macrophages and the consequences of the cellular responses on the conversion machinery. Recombinant TgCyp18 induced the production of nitric oxide (NO), interleukin-12 (IL-12), and tumor necrosis factor alpha through its binding with cysteine-cysteine chemokine receptor 5 (CCR5) and the production of gamma interferon and IL-6 in a CCR5-independent manner. Interestingly, the treatment of macrophages with TgCyp18 resulted in the inhibition of parasite growth and an enhancement of the conversion into bradyzoites via NO in a CCR5-dependent manner. In conclusion, T. gondii possesses sophisticated mechanisms to manipulate host cell responses in a TgCyp18-mediated process.

Download Full-text

Caveolin-1-Deficient Mice Show Defects in Innate Immunity and Inflammatory Immune Response during Salmonella enterica Serovar Typhimurium Infection

Infection and Immunity ◽

10.1128/iai.00949-06 ◽

2006 ◽

Vol 74 (12) ◽

pp. 6665-6674 ◽

Cited By ~ 57

Author(s):

Freddy A. Medina ◽

Cecilia J. de Almeida ◽

Elliott Dew ◽

Jiangwei Li ◽

Gloria Bonuccelli ◽

...

Keyword(s):

Nitric Oxide ◽

Salmonella Enterica ◽

Inflammatory Responses ◽

Systemic Infection ◽

Bacterial Invasion ◽

Chemokine Production ◽

Caveolin 1 ◽

Serovar Typhimurium ◽

Deficient Mice

ABSTRACT A number of studies have shown an association of pathogens with caveolae. To this date, however, there are no studies showing a role for caveolin-1 in modulating immune responses against pathogens. Interestingly, expression of caveolin-1 has been shown to occur in a regulated manner in immune cells in response to lipopolysaccharide (LPS). Here, we sought to determine the role of caveolin-1 (Cav-1) expression in Salmonella pathogenesis. Cav-1−/− mice displayed a significant decrease in survival when challenged with Salmonella enterica serovar Typhimurium. Spleen and tissue burdens were significantly higher in Cav-1−/− mice. However, infection of Cav-1−/− macrophages with serovar Typhimurium did not result in differences in bacterial invasion. In addition, Cav-1−/− mice displayed increased production of inflammatory cytokines, chemokines, and nitric oxide. Regardless of this, Cav-1−/− mice were unable to control the systemic infection of Salmonella. The increased chemokine production in Cav-1−/− mice resulted in greater infiltration of neutrophils into granulomas but did not alter the number of granulomas present. This was accompanied by increased necrosis in the liver. However, Cav-1−/− macrophages displayed increased inflammatory responses and increased nitric oxide production in vitro in response to Salmonella LPS. These results show that caveolin-1 plays a key role in regulating anti-inflammatory responses in macrophages. Taken together, these data suggest that the increased production of toxic mediators from macrophages lacking caveolin-1 is likely to be responsible for the marked susceptibility of caveolin-1-deficient mice to S. enterica serovar Typhimurium.

Download Full-text

The role of TLR-4 in the immunomodulatory effects of recombinant BCG expressing MSP-1C of Plasmodium falciparum

The Journal of Infection in Developing Countries ◽

10.3855/jidc.11331 ◽

2019 ◽

Vol 13 (11) ◽

pp. 1057-1061

Author(s):

Muhammad Adamu Abbas ◽

Rapeah Suppian

Keyword(s):

Nitric Oxide ◽

Plasmodium Falciparum ◽

Inflammatory Responses ◽

Peritoneal Macrophages ◽

Significant Inhibition ◽

Immunomodulatory Effects ◽

Attachment Mechanism ◽

Significant Production ◽

Recombinant Bcg

Introduction: An earlier constructed recombinant BCG expressing the MSP-1C of Plasmodium falciparum, induced inflammatory responses leading to significant production of nitric oxide (NO) alongside higher expression of the enzyme inducible nitric oxide synthase (iNOS) and significant production of the regulatory cytokine, IL-10, indicating significant immunomodulatory effects of the construct. The mechanism of these responses had not been established but is thought to involve toll-like receptor 4 (TLR-4). Methodology: The present study was carried out to determine the role of TLR-4 on eliciting the immunomodulatory effects of recombinant BCG expressing MSP-1C of Plasmodium falciparum leading to the production of NO and IL-10, as well as the expression of iNOS. Six groups of mice (n = 6 per group) were immunised thrice, three weeks apart with intraperitoneal phosphate buffered saline T80 (PBS-T80), BCG or rBCG in the presence or absence of a TLR-4 inhibitor; TAK-242, given one hour prior to each immunisation. Peritoneal macrophages were harvested from the mice and cultured for the determination of NO, iNOS and IL-10 via Griess assay, ELISA and Western blot respectively. Results: The results showed significant inhibition of the production of NO and IL-10 and the expression of iNOS in all groups of mice in the presence of TAK-242. Conclusions: These results presented evidence of the role of TLR-4/rBCG attachment mechanism in modulating the production of NO and IL-10 and the expression of iNOS in response to our rBCG-based malaria vaccine candidate expressing MSP-1C of P. falciparum.

Download Full-text

Abstract 153: Bile Acid Receptor TGR5 Agonism Represents Anti-inflammatory Effects via Stimulating Nitric Oxide Production in Vascular Endothelial Cells

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a153 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Taiki Kida ◽

Yoshiki Tsubosaka ◽

Masatoshi Hori ◽

Hiroshi Ozaki ◽

Takahisa Murata

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Bile Acids ◽

Inflammatory Responses ◽

Vascular Endothelial Cells ◽

Lithocholic Acid ◽

Signal Pathways ◽

No Production ◽

Vascular Endothelial ◽

Anti Inflammatory

Objective TGR5, a membrane-bound, G-protein-coupled receptor for bile acids, is known to be involved in regulation of energy homeostasis and inflammation. However, little is known about the function of TGR5 in vascular endothelial cells. In the present study, we examined whether TGR5 agonism represents anti-inflammatory effects in vascular endothelial cells focusing on nitric oxide (NO) production. Methods and Results In human umbilical vein endothelial cells (HUVECs), treatment with taurolithocholic acid (TLCA), which has the highest affinity to TGR5 among various bile acids, significantly reduced tumor necrosis factor (TNF)-α-induced vascular cell adhesion molecule (VCAM)-1 protein expression and adhesion of human monocytes, U937. These effects were abrogated by a NO synthase (NOS) inhibitor, N G -Monomethyl-L-arginine (L-NMMA). In bovine aortic endothelial cells (BAECs), treatment with TLCA as well as lithocholic acid, which also has high affinity to TGR5, significantly increased the NO production. In contrast, deoxycholic acid and chenodeoxycholic acid, which possess low affinity to TGR5, did not affect the NO production. Gene depletion of TGR5 by siRNA transfection abolished TLCA-induced NO production in BAECs. TLCA-induced NO production was also observed in HUVECs measured as intracellular cGMP accumulation. We next investigated the signal pathways responsible for the TLCA-induced NO production in endothelial cells. Treatment with TLCA increased endothelial NOS (eNOS) ser1177 phosphorylation in HUVECs. This response was accompanied by increased Akt ser473 phosphorylation and intracellular Ca 2+ ([Ca 2+ ] i ). Treatment with phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, or blockade of calcium channel with La 3+ , significantly decreased TLCA-induced eNOS ser1177 phosphorylation and subsequent NO production. Conclusion These results indicate that TGR5 agonism can mediate anti-inflammatory responses by suppressing VCAM-1 expression and monocytes adhesion to endothelial cells. This function is dependent on NO production via Akt activation and [Ca 2+ ] i increase.

Download Full-text

Protocatechuic Aldehyde Attenuates UVA-induced Photoaging in Human Dermal Fibroblast Cells by Suppressing MAPKs/AP-1 and NF-κB Signaling Pathways

International Journal of Molecular Sciences ◽

10.3390/ijms21134619 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4619

Author(s):

Yuling Ding ◽

Chanipa Jiratchayamaethasakul ◽

Seung-Hong Lee

Keyword(s):

Nitric Oxide ◽

Protective Effect ◽

Signaling Pathways ◽

Inflammatory Responses ◽

Dermal Fibroblast ◽

Human Dermal Fibroblast ◽

Potential Candidate ◽

Ros Scavenging ◽

Protocatechuic Aldehyde ◽

Hdf Cells

Ultraviolet radiation (UV) is a major causative factor of DNA damage, inflammatory responses, reactive oxygen species (ROS) generation and a turnover of various cutaneous lesions resulting in skin photoaging. The purpose of this study is to investigate the protective effect of protocatechuic aldehyde (PA), which is a nature-derived compound, against UVA-induced photoaging by using human dermal fibroblast (HDF) cells. In this study, our results indicated that PA significantly reduced the levels of intracellular ROS, nitric oxide (NO), and prostaglandins-E2 (PGE2) in UVA-irradiated HDF cells. It also inhibited the levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. Besides, PA significantly suppressed the expression of matrix metalloproteinases-1 (MMP-1) and pro-inflammatory cytokines and promoted collagen synthesis in the UVA-irradiated HDF cells. These events occurred through the regulation of activator protein 1 (AP-1), nuclear factor-κB (NF-κB), and p38 signaling pathways in UVA-irradiated HDF cells. Our findings suggest that PA enhances the protective effect of UVA-irradiated photoaging, which is associated with ROS scavenging, anti-wrinkle, and anti-inflammatory activities. Therefore, PA can be a potential candidate for the provision of a protective effect against UVA-stimulated photoaging in the pharmaceutical and cosmeceutical industries.

Download Full-text