Acute pancreatitis is an initially localized inflammation of the pancreatic gland. The precise mechanisms by which aetiological factors induce acute pancreatitis are not yet known, but when initiated, common inflammatory pathways seem to be involved, with cytokines being their components of major importance. The inducible nitric oxide synthase gene (iNOS) encodes an enzyme involved in the pathway of reactive oxygen species and induced in response to infection, cytokines. iNOS is capable of generating large quantities of nitric oxide produced during inflammation. The objective of this study was to investigate the association between acute pancreatitis risk and iNOS polymorphisms. The studied single-nucleotide polymorphisms (SNPs) were Ser608Leu, resulting in an amino acid substitution, and 1173C/T and 954G/C, both in the gene promoter region that is linked to increased enzyme expression, leading to higher NO production. The genotypes for the three SNPs were determined in 93 patients with acute pancreatitis and 60 controls without pancreatitis or cancer that were matched for age and gender. Data analysis was done by conditional logistic regression. It was found that the Ser608Leu polymorphism was more frequent among cases with acute pancreatitis compared to controls (OR = 2.88; 95% CI: 1.49-5.57; P = 0.002), although no individually statistically significant associations for the other SNPs studied were detected. We suggest that iNOS Ser608Leu can be used as a marker to define the risk of acute pancreatitis.
- MeSH
- Acute Disease MeSH
- Gene Frequency genetics MeSH
- Genetic Predisposition to Disease * MeSH
- Polymorphism, Single Nucleotide genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Pancreatitis enzymology genetics MeSH
- Risk Factors MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Amino Acid Substitution genetics MeSH
- Nitric Oxide Synthase Type II genetics MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Pathogenesis of hypoxic pulmonary hypertension is initiated by oxidative injury to the pulmonary vascular wall. Because nitric oxide (NO) can contribute to oxidative stress and because the inducible isoform of NO synthase (iNOS) is often upregulated in association with tissue injury, we hypothesized that iNOS-derived NO participates in the pulmonary vascular wall injury at the onset of hypoxic pulmonary hypertension. An effective and selective dose of an iNOS inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL), for chronic peroral treatment was first determined (8 mg/l in drinking water) by measuring exhaled NO concentration and systemic arterial pressure after LPS injection under ketamine+xylazine anesthesia. A separate batch of rats was then exposed to hypoxia (10% O2) and given L-NIL or a nonselective inhibitor of all NO synthases, N(G)-nitro-L-arginine methyl ester (L-NAME, 500 mg/l), in drinking water. Both inhibitors, applied just before and during 1-wk hypoxia, equally reduced pulmonary arterial pressure (PAP) measured under ketamine+xylazine anesthesia. If hypoxia continued for 2 more wk after L-NIL treatment was discontinued, PAP was still lower than in untreated hypoxic controls. Immunostaining of lung vessels showed negligible iNOS presence in control rats, striking iNOS expression after 4 days of hypoxia, and return of iNOS immunostaining toward normally low levels after 20 days of hypoxia. Lung NO production, measured as NO concentration in exhaled air, was markedly elevated as early as on the first day of hypoxia. We conclude that transient iNOS induction in the pulmonary vascular wall at the beginning of chronic hypoxia participates in the pathogenesis of pulmonary hypertension.
- MeSH
- Administration, Oral MeSH
- Pulmonary Artery enzymology MeSH
- Time Factors MeSH
- Chronic Disease MeSH
- Financing, Organized MeSH
- Hypoxia MeSH
- Enzyme Inhibitors administration & dosage pharmacology MeSH
- Rats MeSH
- Lysine administration & dosage pharmacology MeSH
- NG-Nitroarginine Methyl Ester pharmacology MeSH
- Nitric Oxide MeSH
- Lung metabolism MeSH
- Hypertension, Pulmonary etiology physiopathology MeSH
- Rats, Wistar MeSH
- Nitric Oxide Synthase Type II antagonists & inhibitors biosynthesis MeSH
- Exhalation MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
The current study was designed to investigate the effect of berbamine (BBM) on isoproterenol (ISO) induced changes in cardiac marker enzymes, myocardial oxidative stress, lipid profile and expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in male Wistar rats. Rats were pretreated with BBM (25 mg/kg) through intraperitoneal injection for 7 days followed by induction of myocardial infarction (MI) by subcutaneous injection of ISO (85 mg/kg) for last two days. Key findings: In the present study, the histopathological findings of the heart tissue showed that BBM treatment significantly minimized the damage induced by ISO. BBM pretreatment showed a significant decrease in heart weight, serum marker enzymes, lipid peroxidation and significant increase in cardiac endogenous enzymatic and non-enzymatic antioxidants compared to the ISO-treated group. In addition, we observed significantly upregulated eNOS expression and downregulated iNOS expression in BBM pretreated group. Thus, BBM protected the rat’s heart from ISO-induced myocardial infarction by its antioxidant, and antilipidemic properties. Significance: The results of the present investigation suggested that BBM efficiently ameliorated the ISO-induced myocardial infarction in rats.
- MeSH
- Benzylisoquinolines administration & dosage pharmacology MeSH
- Myocardial Infarction drug therapy chemically induced physiopathology MeSH
- Isoproterenol administration & dosage adverse effects MeSH
- Cardiotonic Agents MeSH
- Disease Models, Animal MeSH
- Nitrosative Stress drug effects MeSH
- Polymerase Chain Reaction methods MeSH
- Rats, Wistar MeSH
- Nitric Oxide Synthase Type II drug effects MeSH
- Nitric Oxide Synthase Type III drug effects MeSH
- In Vitro Techniques MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
OBJECTIVE: Nitric oxide is an important vasoactive mediator. Changes in NO production, caused by functional variants of both endothelial and inducible NO synthase (eNOS, iNOS), might play a role in portal hypertension. The aim was to study the significance of functional eNOS and iNOS gene variants in cirrhotic patients and their interrelationship to both inflammatory and endothelial activation parameters. MATERIAL AND METHODS: One hundred and thirty-two patients with liver cirrhosis (age 36-72 years) and 101 controls were examined for functional variants of eNOS (E298D, 27bpintr4, 786T/C) and iNOS (R221W, S608L) genes. Inflammatory (IL6, IL8, IL10) and vasoactive (sVCAM-1, E-selectin) cytokines were measured using ELISA kits. RESULTS: The frequency of E298D (GG 12%, GT 41%, TT 47%), 28bpintr4 (AA 6%, AB 28%, BB 66%), 786T/C genotypes (CC 17%, CT 45%, TT 38%), as well as R221W (CC 93%, CT 7%, TT 0%), and S608L (CC 65%, CT 32%, TT 3%) genotypes in cirrhotic patients did not differ from the controls (p > 0.05 for all comparisons). No relationship was found between the frequency of these genotypes and the severity of portal hypertension, or either inflammatory or vasoactive cytokines. A positive correlation was found between hepatic venous pressure gradient and cytokine concentration: sVCAM-1, IL6, IL8, IL10. CONCLUSIONS: Examined eNOS and iNOS variants have no relationship to pathogenesis of liver cirrhosis. Severity of portal hypertension was associated with the changes in endothelial activation.
- MeSH
- Cytokines blood MeSH
- DNA Primers chemistry MeSH
- Adult MeSH
- Enzyme-Linked Immunosorbent Assay MeSH
- Genetic Variation MeSH
- Genotype MeSH
- Liver Cirrhosis complications genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Polymerase Chain Reaction methods MeSH
- Hypertension, Portal etiology genetics MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Severity of Illness Index MeSH
- Nitric Oxide Synthase Type II genetics MeSH
- Nitric Oxide Synthase Type III genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The aim of this study was to investigate longitudinal changes of the pulmonary inflammatory process as a result of mechanical stress due to mechanical ventilation. The concentrations of IL-8, TNF-α, MIP-1β, nitrites/nitrates, and inducible nitric oxide synthases (iNOS) were investigated indicate in bronchoalveolar lavage (BAL). Twenty-three piglets were divided into three groups. Group I: animals breathing spontaneously; group II: mechanical ventilation (tidal volume (TV) = 7 mL/kg, PEEP = 5 cmH(2)O); group III: mechanical ventilation (TV = 15 mL/kg, PEEP = 0 cmH(2)0). Concentrations of BAL nitrites/nitrates from groups II and III increased during the first hour of mechanical ventilation (P = .03 and .02, respectively). The highest expression of iNOS was observed during the first hour in groups II and III. IL-8 concentration increased significantly in groups II and III. Production of TNF-α increased significantly in group III during the second and third hour (P = .01). Concentration of MIP-1β was significantly increased in groups II and III after the first hour (P = .012 and P = .008, respectively).
- MeSH
- Acute Lung Injury etiology metabolism MeSH
- Bronchoalveolar Lavage Fluid chemistry cytology MeSH
- Chemokine CCL4 metabolism MeSH
- Cytokines metabolism MeSH
- Tidal Volume MeSH
- Nitrates metabolism MeSH
- Nitrites metabolism MeSH
- Interleukin-8 metabolism MeSH
- Lung metabolism pathology physiopathology MeSH
- Pulmonary Alveoli metabolism pathology MeSH
- Lung Compliance physiology MeSH
- Swine MeSH
- Nitric Oxide Synthase Type II metabolism MeSH
- Tumor Necrosis Factor-alpha metabolism MeSH
- Respiration, Artificial adverse effects MeSH
- Positive-Pressure Respiration instrumentation MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Nasal polyps (NP), edematous projections of nasal mucosa (NM), are characterized by an inflammatory cellular infiltrate, however, little is known about etiopathogenesis of NP. Both innate immune mechanisms leading to activation of NF-kappaB and homeostasis of epithelial cells were implicated in the pathogenesis of NP. In this study we investigated the expression of insulin-like growth factor-1 receptor (IGF-1R) and inducible nitric-oxide synthase (iNOS) in NP compared to healthy NM in both the epithelial and stromal compartments. Using immunohistochemistry, frozen tissue sections of NP from 18 patients, and mucosal biopsy specimens of the inferior turbinate from 17 subjects were stained for IGF-1R and iNOS markers. Fluorescence microscopy and computerized image analysis revealed low numbers of IGF-1R-positive cells in all specimens. However, substantially increased numbers of IGF-1R-positive cells were found in NP compared to NM both within the epithelium (1.63 vs. 0.43) and stroma (3.27 vs. 1.03). Positivity for iNOS was detected within the epithelium of NP compared with NM. Numbers of iNOS-positive single cells were highly increased in NP vs. NM in both epithelial (3.83 vs. 1.08) and stromal (4.96 vs. 2.67) compartments. An increased iNOS expression within the epithelial layer as well as increased number of iNOS- and IGF-1R-positive cells in NP was observed. This suggests that innate immune mechanism, and to a lesser extent also growth and homeostasis of epithelial cells, may play a role in formation of NP.
- MeSH
- Biopsy MeSH
- Stromal Cells immunology metabolism pathology MeSH
- Cytokines metabolism MeSH
- Epithelial Cells immunology metabolism pathology MeSH
- Microscopy, Fluorescence MeSH
- Homeostasis MeSH
- Single-Blind Method MeSH
- Humans MeSH
- NF-kappa B metabolism MeSH
- Nasal Polyps etiology chemistry immunology MeSH
- Nasal Mucosa chemistry MeSH
- Immunity, Innate MeSH
- Receptor, IGF Type 1 analysis MeSH
- Nitric Oxide Synthase Type II analysis MeSH
- Environmental Exposure MeSH
- Check Tag
- Humans MeSH
viii, 78 s. : il., tab.
Valsartan has the potential to attenuate neointimal hyperplasia and to suppress the inflammatory response. This study aimed to evaluate the role of valsartan in neointimal hyperplasia and the toll-like receptor 4 (TLR4)-nitric oxide synthase (NOS) pathway in the balloon-injured rat aorta.Forty-eight Wistar rats were randomly allocated to three groups: sham control (control), balloon-injured group (surgery), and balloon-injured+valsartan-treated group (valsartan). Rats were killed at 14 and 28 days after balloon-injury, and then the aortic tissues were collected for morphometric analysis as well as for measurements of the mRNA or protein expression of angiotensin II, angiotensin II type 1 (AT1) receptor, angiotensin II type 2 (AT2) receptor, TLR4, endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), serine/arginine-rich splicing factor 1(SRSF1) and extracellular signal regulated kinase (ERK). Valsartan at a dose of 20 mg/kg/day markedly decreased neointimal hyperplasia in the aorta of balloon-injured rats, and significantly reduced the mRNA or protein expression of TLR4, AT1 receptor, SRSF1 and phosphorylated-ERK (p-ERK) as well as the aortic levels of iNOS (all p < 0.05). Moreover, valsartan increased the eNOS level and AT2 receptor mRNA and protein expression levels (all p < 0.05). Valsartan prevented neointimal hyperplasia and inhibited SRSF1 expression and the TLR4-iNOS-ERK-AT1 receptor pathway in the balloon-injured rat aorta.
- MeSH
- Aorta drug effects enzymology pathology MeSH
- Angiotensin II Type 1 Receptor Blockers pharmacology MeSH
- Extracellular Signal-Regulated MAP Kinases metabolism MeSH
- Phosphorylation MeSH
- Hyperplasia MeSH
- Disease Models, Animal MeSH
- Aortic Diseases drug therapy enzymology genetics pathology MeSH
- Neointima * MeSH
- Vascular System Injuries drug therapy enzymology genetics pathology MeSH
- Rats, Wistar MeSH
- Receptor, Angiotensin, Type 1 genetics metabolism MeSH
- Serine-Arginine Splicing Factors metabolism MeSH
- Signal Transduction MeSH
- Nitric Oxide Synthase Type II metabolism MeSH
- Toll-Like Receptor 4 genetics metabolism MeSH
- Valsartan pharmacology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
We studied anxiety-like behavior in the elevated plus-maze (EPM) tests in male Lewis rats on days 2 and 4 of adjuvant arthritis (AA). In plasma we analyzed C-reactive protein (CRP), albumin, ACTH, corticosterone, in the hippocampus the mRNA expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), corticotrophin releasing factor (CRH), NADPH oxidases NOX1 and NOX2, and inducible NO-synthase (iNOS). EPM tests showed a higher anxiety index in AA rats on days 2 and 4 and reduction of total entries. On days 2 and 4 we found reduced plasma albumin, enhanced CRP, ACTH and corticosterone, and in the hippocampus enhanced mRNA for NOX1 and IL-1β in AA rats, on day 4 we found enhanced mRNAs for iNOS and IL-6, and reduced mRNA for CRH. The mRNA for NOX2 did not change on any experimental day. These results suggest enhanced anxiety, as well as locomotor impairment during the early phase of AA that correlate with enhanced mRNA expressions of parameters of oxidative stress NOX1, iNOS, and inflammatory cytokines IL-1β and IL-6 in the hippocampus.
- MeSH
- Arthritis, Experimental complications metabolism psychology MeSH
- Maze Learning physiology MeSH
- Hippocampus metabolism MeSH
- Interleukin-1beta biosynthesis MeSH
- Interleukin-6 biosynthesis MeSH
- Rats MeSH
- RNA, Messenger biosynthesis MeSH
- NADH, NADPH Oxidoreductases biosynthesis MeSH
- Rats, Inbred Lew MeSH
- Nitric Oxide Synthase Type II biosynthesis MeSH
- Anxiety complications metabolism psychology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
Two major effector systems are frequently implicated in the immune and endothelial cell alternations associated with inflammation. They include the enhanced production of reactive oxygen species and diminished bioavailability of nitric oxide (NO). Importantly, these processes can be regulated by endogenously produced methylarginines, inhibitors for NO derived from macrophages and endothelial cells. Therefore, the aim of this study was to show the potential pharmacological intervention of methylarginines (N(G)-methyl-L-arginine, L-NMMA; N(G), N(G)'-dimethyl-L-arginine-symmetric dimethylarginine, SDMA; and N(G), N(G)-dimethyl-L-arginine-asymmetric dimethylarginine, ADMA) in activation of murine peritoneal (RAW 264.7) and alveolar (MHS) macrophages with lipopolysaccharide from Gram-negative bacteria (LPS). The data presented in this study clearly declare that L-NMMA (1-50μM) and ADMA (10-50 μM) significantly inhibited the LPS-induced NO production from macrophages in a concentration-dependent manner. It was demonstrated, for the first time, that the ADMA- and L-NMMA-induced down regulation of NO production was accompanied by reduced expression of mRNA and protein for inducible NO synthase as well as decreased activation of nuclear factor-κB. Importantly, we found a negative correlation between the ADMA-dependent reduction of NO production and ADMA-increased superoxide formation, which indicates that ADMA can negatively affect the balance in LPS-induced macrophage-derived production of reactive mediators. The only effect of SDMA was observed for LPS-triggered superoxide production, which was significantly decreased in its highest concentration (50 μM). In summary, L-NMMA and ADMA can mediate their effects on macrophage activation via regulation of intracellular signaling pathways, which can affect critical functions in activated macrophages.
- MeSH
- Macrophages, Alveolar drug effects immunology metabolism MeSH
- Arginine analogs & derivatives chemistry pharmacology MeSH
- Cell Culture Techniques MeSH
- Cell Line MeSH
- Gene Expression drug effects MeSH
- Lipopolysaccharides toxicity MeSH
- Mice MeSH
- NF-kappa B antagonists & inhibitors biosynthesis genetics MeSH
- Nitric Oxide biosynthesis MeSH
- Macrophages, Peritoneal drug effects immunology metabolism MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Superoxides metabolism MeSH
- Nitric Oxide Synthase Type II antagonists & inhibitors biosynthesis genetics MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Blotting, Western MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
