Nitric Oxide In Pathogenesis Research Articles

Overexpression of Inducible Nitric Oxide Synthase in Allergic and Nonallergic Nasal Polyp.

Sinonasal polyps are very common benign lesions of the nasal mucosa. Most of nasal polyps (NP) are idiopathic, and the pathophysiology of this disease is still incompletely understood. Nitric oxide (NO) is a reactive molecule generated by nitric oxide synthase (NOS). NO has been identified as an important mediator in airway function and pathogenesis of several respiratory system diseases. Histological and genetical expression of iNOS was detected to evaluate the role of NO in the pathogenesis of allergic (ANP) and nonallergic nasal polyps (NANP). Forty patients with nasal polyps (20 allergic and 20 nonallergic) were identified by history, clinical examination, and investigation. NPs were obtained from the middle turbinate (MT) during concha bullosa surgery. Twenty normal MT nasal tissues were taken as the control from patients undergoing concha bullosa surgery, without any evidence of allergy or inflammation. A nasal polyp specimen from each patient was subjected for immune-histochemical study followed by histological examination to detect the expression of iNOS. RT-PCR was used to evaluate the iNOS gene expression in isolated tissues. The expression of iNOS in both epithelial and stromal layers was greater in NP than in MT tissues. The ANP group showed more iNOS expression than those of the NANP group. The relative mRNA levels of iNOS gene were significantly higher in ANP (2.5-fold) compared to the normal (1.02-fold, P < 0.001) and NANP (1.5-fold, P < 0.01) groups. NP exhibited a significantly high expression of iNOS at both histological and genetical levels. NO might be an essential factor in the life history of NP. Further studies in a larger sample size are required to explain the probable mechanisms of NO in pathogenesis of NP.

Role of nitric oxide in pathogenesis of tumor growth and its possible application in cancer treatment.

In this review, the role of nitric oxide (NO) in the pathogenesis of the tumor growth and possibilities of its application in the treatment of cancer patients are analyzed. NO is one of the most important mediators of physiological processes being involved in the regulation of practically all body functions in health and disease. The role of NO in the development of many pathological conditions has been extensively studied and debated in recent years. Today it is clear that NO in relation to malignant tumors may exhibit a dual activity- can stimulate tumor growth and cause an opposite antitumor effect. Effects of NO are mostly dependent on its concentration. At low concentrations, NO could inhibit apoptosis and cause mutations that potentially lead to the formation of malignant growth loci. However, a high concentration of NO appears to be detrimental to malignant cells, in particular under conditions of simultaneous exposure to ionizing radiation. In humans, the inducible NO synthase (iNOS, type II) is the most powerful form of NO synthases (NOS) and has the ability to synthesize large amounts of NO for a long time and exert a protective function. iNOS is expressed in macrophages, monocytes, neutrophils, fibroblasts, hepatocytes, and other cell types. In tissue of malignant tumors, the macrophagal iNOS is the main form. Experimental data provide an evidence that activated macrophages and leukocytes, which are the part of peritumorous inflammatory infiltrate, can provide radiosensitization of tumors by direct synthesis of NO and indirectly- through the secretion of cytokines stimulating iNOS activity in cancer cells. Such approach could be useful for the development of new schemes and methods of anticancer therapy based on the activation of endogenous NO biosynthesis pathways.

Nitric oxide synthase 2 augments the survival of mice upon Salmonella Typhimurium infection induced sepsis: impact on innate immune responses &amp; organ damage

Abstract Sepsis is defined as infection induced deregulation of host immune responses that may lead to multi organ dysfunction. Enhanced inflammation and persistent organ damage often leads to impaired recovery and death of sepsis patients. Thus molecules that attenuate inflammatory responses are potential therapeutic targets for sepsis. We have established intra-peritoneal S. Typhimurium infection induced peritonitis model of sepsis in mice characterized by: enhanced amounts of nitric oxide (NO), ROS, cytokines, neutrophil recruitment at the site of infection, organ damage and death of mice. Nitric oxide (NO), a highly reactive molecule has pleiotropic effects in host ranging from cell signaling and gene modulation to antimicrobial effects. Enhanced activity of Nos2 and NO is seen in sepsis patients. However, the roles of NO in pathogenesis of sepsis are controversial. Using Nos2−/− mice we attempted to elucidate the roles of Nos2 derived NO in sepsis. Upon infection Nos2−/− mice showed attenuated induction of ROS, pro-inflammatory cytokines and neutrophil recruitment. Importantly, dampened innate immune responses in Nos2−/− mice correlated with increased microbial burden, liver damage, cardiac dysfunction and reduced survival upon sepsis. Clearly Nos2 derived NO promotes protective innate immune responses during sepsis. The precise role of Nos2 derived NO was further evaluated by exogenous supplementation of Nos2−/− mice with a NO donor. Administration of exogenous NO in Nos2−/− mice beneficially restored host innate immune responses and increased survival. Our findings are crucial in the context of therapeutic interventions for sepsis and the implications for NO as a target molecule are discussed.

Погляд терапевта на лікування гострого вірусного риніту у вагітних

У статті проаналізовано вплив гострих респіраторних інфекцій протягом вагітності. Особлива увага приділяється впливу синдрому ендогенної інтоксикації та обґрунтуванню вибору для його дослідження. Проаналізовано й описано роль оксиду азоту в патогенезі запального та імунного процесів при вагітності, ускладненій гострою респіраторною вірусною інфекцією. Приділено увагу особливим вимогам при лікуванні цієї категорії пацієнток. Запропоновано спосіб лікування гострого вірусного риніту у вагітних шляхом застосування комбінації препаратів енгістол і синупрет. Встановлено, що проведення комплексного лікування вагітних із гострою респіраторною вірусною інфекцією, гострим ринітом із застосуванням препарату енгістол у комбінації з препаратом рослинного походження синупрет має патогенетичну спрямованість завдяки протизапальній, дезінтоксикаційній, противірусній, антигістамінній і імуномодулюючій властивостям препаратів.Нами встановлено, що серед інших методів лікування гострої респіраторної вірусної інфекції у вагітних запропонована терапія є високоефективною, не має побічних ефектів і добре переноситься вагітними жінками. Спосіб доступний, не завдає шкоди, сприяє оптимізації лікування вагітних, забезпечує його доцільність й можливість масового використання.

Concentrations of nitric oxide metabolites in the serum of Iranian multiple sclerosis patients

Nitric oxide is a signaling molecule that has various roles under normal conditions, notably in relation to vasodilation, neuronal function, and immune responses. Additionally, it has been implicated in some pathological states including multiple sclerosis. Multiple sclerosis is characterized by chronic inflammation and oligodendrocyte and axonal damage and ultimately death of neurons. The precise role of nitric oxide in pathogenesis is confounded by its opposing beneficial and deleterious effects. With respect to multiple sclerosis, increased nitric oxide metabolites have been well documented in the cerebrospinal fluid of patients. Reports on changes in the concentration of nitric oxide in the serum of patients have been inconsistent. Here, we report statistically significant increases in the concentrations of nitric oxide metabolites in the serum of multiple sclerosis patients not under medications from two subpopulations in Iran, supporting contentions that disease status does correlate with nitric oxide levels in this easily accessible body fluid. However, the tightness of the correlation appears to be insufficient to allow it to be used as an independent surrogate for assessment of disease status.

Role of nitric oxide in pathogenesis of cold nerve injury

To study the role of nitric oxide (NO) in the pathogenesis of cold nerve injury and to explore its mechanism. Cold nerve injury model was established in rat's sciatic nerve. Consistent and intermittent cooling of 4 degrees C for 2 hours were respectively applied to the sciatic nerves. Nerve samples were taken at different time points: immediately post-cooling and 4 h, 1 d & 3 d post-cooling. The group of aminoguanidine (AG) intervention was also established. Then NO levels in the nerves and blood serum were detected. Induced nitric oxide synthase (iNOS) in ganglion was determined by immunohistochemistry. Morphology of cooled sciatic nerves in the AG groups (consistent & intermittent cooling AG groups) and control groups (1 d time point of consistent & intermittent cooling groups) was observed by light microscope and electron microscope. At the time points of immediacy, 4 h, 3 d in the consistent cooling groups and the time points of immediacy, 4 h, 1 d in the intermittent cooling groups, different incremental degrees of NO levels in the cooled nerves (0.146 +/- 0.047), (0.216 +/- 0.048), (0.137 +/- 0.035), (0.154 +/- 0.027), (0.260 +/- 0.027), (0.218 +/- 0.042) micromol/g as compared with those of controls (0.098 +/- 0.022), (0.158 +/- 0.030), (0.085 +/- 0.020), (0.127 +/- 0.016), (0.72 +/- 0.027), (0.174 +/- 0.026) micromol/g, P < 0.01, P < 0.05). And NO levels in the cooled nerves at the time points of 4 h, 1 d, 3 d in the intermittent cooling groups were higher than those in the consistent cooling groups (P < 0.01, P < 0.05). NO levels in blood serum at the time points of immediacy and 1 d in the intermittent cooling groups (4.98 +/- 1.33) micromol/L, (4.02 +/- 0.68) micromol/L were higher than those in the consistent cooling groups (2.47 +/- 0.36) micromol/L, (3.00 +/- 0.67) micromol/L, P < 0.01). Both in consistent cooling and intermittent cooling groups, different incremental degrees of areas and integrated optical density (IOD) of iNOS positive staining in ganglions were found in cooled side as compared with the control side at different time points (P < 0.01, P < 0.05, P > 0.05), while those at the time point of immediacy in the intermittent cooling groups (131 686 +/- 24 549) , (4.1 +/- 0.13) x 10(9) were higher than those in the consistent cooling groups (78 558 +/- 34 849), (2.1 +/- 0.93) x 10(9), P < 0.05. NO level of cooled nerves in the intermittent cooling AG group (0.178 +/- 0.030) micromol/g was lower than those at the time point of 1 d in intermittent cooling groups (0.218 +/- 0.042) micromol/g, P < 0.05). Also a reduction of NO levels of blood serum, areas and IOD of iNOS positive staining was found in the AG groups as compared with the control groups (P < 0.05) while the reduction was more significantly found in the intermittent cooling AG group (P < 0.01, P < 0.05). Through light microscope and electron microscope, more severe pathological injury of cooled nerve was seen in the intermittent cooling group as compared with 1d time point of the consistent cooling groups, and a marked reduction of pathological injury was found when AG was administered. It was also more significant in the intermittent cooling AG group. NO plays a causative role in the pathogenesis of cold nerve injury, especially in intermittent cold nerve injury. The expression of iNOS is the main source of NO. Production of free radicals and the resulting toxic injury may be its main mechanism.

Nitric oxide and virus infection.

Nitric oxide (NO) has complex and diverse functions in physiological and pathophysiological phenomena. The mechanisms of many events induced by NO are now well defined, so that a fundamental understanding of NO biology is almost established. Accumulated evidence suggests that NO and oxygen radicals such as superoxide are key molecules in the pathogenesis of various infectious diseases. NO biosynthesis, particularly through expression of an inducible NO synthase (iNOS), occurs in a variety of microbial infections. Although antimicrobial activity of NO is appreciated for bacteria and protozoa, NO has opposing effects in virus infections such as influenza virus pneumonia and certain other neurotropic virus infections. iNOS produces an excessive amount of NO for long periods, which allows generation of a highly reactive nitrogen oxide species, peroxynitrite, via a radical coupling reaction of NO with superoxide. Thus, peroxynitrite causes oxidative tissue injury through potent oxidation and nitration reactions of various biomolecules. NO also appears to affect a host's immune response, with immunopathological consequences. For example, overproduction of NO in virus infections in mice is reported to suppress type 1 helper T-cell-dependent immune responses, leading to type 2 helper T-cell-biased immunological host responses. Thus, NO may be a host response modulator rather than a simple antiviral agent. The unique biological properties of NO are further illustrated by our recent data suggesting that viral mutation and evolution may be accelerated by NO-induced oxidative stress. Here, we discuss these multiple roles of NO in pathogenesis of virus infections as related to both non-specific inflammatory responses and immunological host reactions modulated by NO during infections in vivo.

Inhibition of nitric oxide production exacerbates chronic ocular toxoplasmosis.

There is considerable controversy as to the roles of parasite proliferation and the inflammatory response in destruction of the retina during Toxoplasma gondii infection. A murine model was used to investigate the role of nitric oxide in pathogenesis of chronic ocular toxoplasmosis. Increased quantities of messenger RNA (mRNA) transcripts for iNOS were detected in the eyes of chronically infected C57BL/6 mice compared with noninfected control mice. Inhibition of nitric oxide (NO) by the addition of Lomega-nitro-L-arginine methyl ester (L-NAME) to the drinking water of infected mice between weeks 4-6 of infection, exacerbated ocular inflammation. The amount of inflammation was assessed semiquantitatively in histological sections of the eye. Eyes from L-NAME treated mice showed a significant increase in inflammation of the retina (P = 0.02), choroid (P = 0.03), and vitreous (P = 0.02) compared with control mice. These results demonstrate a protective role for NO in the control of chronic, ocular toxoplasmosis.

Role of Nitric Oxide in Pathogenesis of Herpes Simplex Virus Encephalitis in Rats

The role of nitric oxide (NO) in the pathogenesis of viral encephalitis was investigated by using an experimental model of herpes simplex virus type 1 (HSV-1) encephalitis in Lewis rats. The expression of inducible NO synthase (iNOS) mRNA determined by Northern blotting was observed first in the olfactory bulb and the brain stem on day 5 after intranasal inoculation of HSV-1, and thereafter iNOS mRNA was detected in other brain regions, i.e., cerebrum and cerebellum. In various parts of the brain, excessive NO production was identified by electron spin resonance spectroscopy. The temporal and spatial patterns of iNOS expression coincided with those of viral propagation, as demonstrated by polymerase chain reaction for HSV-1 gene expression as well as by the plaque-forming assay. Immunohistochemical study determined that iNOS was localized mainly in monocyte-derived macrophages. Treatment of virus-infected animals with the NOS inhibitor Nω-monomethyl-l-arginine (l-NMMA), but not Nω-monomethyl-d-arginine, significantly ameliorated not only clinical symptoms such as paralysis and seizures but also mortality. Virus yield from brain tissue was not affected by l-NMMA treatment. It is of interest that increased expression of the antioxidant enzyme heme oxygenase-1 was observed in the HSV-1-infected brain; this increased expression was strongly inhibited by l-NMMA treatment. These data suggest that the high level of NO produced by iNOS is a pathogenic factor in HSV-1-induced encephalitis in rats.

Role of nitric oxide in pathogenesis underlying ischemic cerebral damage.

1. Based upon the intriguing report that nitric oxide synthase (NOS) inhibitor dose-dependently reverses N-methyl-D-aspartate (NMDA)-induced neurotoxicity observed in primary cortical cell cultures, many laboratories have investigated whether NOS inhibition is beneficial as a treatment for cerebral ischemia. 2. Although the results are variable, it is likely thought that nitric oxide plays a key role in pathomechanism underlying ischemic brain damage. 3. We review the experimental studies on effects of NOS inhibition on cerebral ischemia and measuring nitric oxide produced in the brain subjected to cerebral ischemia. 4. Finally, the possibility of NOS inhibitors as a therapeutical tool is discussed.

Role of nitric oxide in pathogenesis of gastric mucosal damage induced by compound [formula omitted] in rats

We examined the effects of various nitric oxide synthase (NOS) inhibitors on development of gastric lesions induced by compound 48 80 ( 48 80 ) in rats and investigated the roles of NO and inducible NOS (iNOS) in inflammatory gastric responses. Animals were given 48 80 (1 mg/kg, ip) once daily for 4 days, and the stomachs were examined for lesions 24 h after the final administration. NOS inhbitors such as L-NAME, L-NMMA, aminoguanidine or dexamethasone were administered for 4 days during 48 80 treatment. The repeated administration of 48 80 caused damage in the stomach with severe edema in the submucosa. These lesions induced by 48 80 were dose-dependently prevented by concurrent administration of L-NAME. The protective effect of L-NAME on 48 80 - induced gastric lesions was mimicked by L-NMMA, aminoguanidine as well as dexamethasone, and significantly antagonized by co-administration of L-arginine but not by D-arginine. Acid secretion was slightly decreased after 48 80 treatment, but was significantly augmented by the combined administration of L-NAME with 48 80 . The mucosal MPO activity, TBA reactants and vascular permeability in the stomach were all increased after 48 80 treatment, but these changes were also significantly mitigated by co-administration of L-NAME. The Ca 2+-independent NOS activity in the mucosa was increased four times during 48 80 treatment, and this change was also inhibited by dexamethasone. These results suggest that: 1) the repeated administration of 48 80 induced inflammatory gastric lesions in the rat stomach; 2) the pathogenic mechanism of these lesions involves endogenous NO produced by iNOS, in addition to oxyradical formation; and 3) the deleterious role of NO during 48 80 treatment may be accounted for by a cytotoxic action of peroxynitrite, which is formed in the presence of NO and superoxide radicals.

Raised antibody titre against conjugated S-nitrosocysteine in IgM paraproteinaemic peripheral, neuropathy: possible role of nitric oxide in pathogenesis.

Raised antibody titre against conjugated S-nitrosocysteine in IgM paraproteinaemic peripheral, neuropathy: possible role of nitric oxide in pathogenesis.