Serum methylarginines and spirometry-measured lung function in older adults

Rationale: Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in animal models of lung disease but have not previously been examined for their association with spirometric measures of lung function in humans. Objectives: This study measured serum concentrations of asymmetric and symmetric dimethylarginine in a representative sample of older community-dwelling adults and determined their association with spirometric lung function measures. Methods: Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and L-arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults from the Hunter Community Study. The five key lung function measures included as outcomes were Forced Expiratory Volume in 1 second, Forced Vital Capacity, Forced Expiratory Volume in 1 second to Forced Vital Capacity ratio, Percent Predicted Forced Expiratory Volume in 1 second, and Percent Predicted Forced Vital Capacity. Measurements and Main Results: In adjusted analyses there were statistically significant independent associations between a) higher asymmetric dimethylarginine, lower Forced Expiratory Volume in 1 second and lower Forced Vital Capacity; and b) lower L-arginine/asymmetric dimethylarginine ratio, lower Forced Expiratory Volume in 1 second, lower Percent Predicted Forced Expiratory Volume in 1 second and lower Percent Predicted Forced Vital Capacity. By contrast, no significant associations were observed between symmetric dimethylarginine and lung function. Conclusions: After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum asymmetric dimethylarginine was independently associated with a reduction in key measures of lung function. Further research is needed to determine if methylarginines predict the decline in lung function

Overexpression of endothelial nitric oxide synthase suppresses features of allergic asthma in mice

BACKGROUND: Asthma is associated with airway hyperresponsiveness and enhanced T-cell number/activity on one hand and increased levels of exhaled nitric oxide (NO) with expression of inducible NO synthase (iNOS) on the other hand. These findings are in paradox, as NO also relaxes airway smooth muscle and has immunosuppressive properties. The exact role of the endothelial NOS (eNOS) isoform in asthma is still unknown. We hypothezised that a delicate regulation in the production of NO and its bioactive forms by eNOS might be the key to the pathogenesis of asthma. METHODS: The contribution of eNOS on the development of asthmatic features was examined. We used transgenic mice that overexpress eNOS and measured characteristic features of allergic asthma after sensitisation and challenge of these mice with the allergen ovalbumin. RESULTS: eNOS overexpression resulted in both increased eNOS activity and NO production in the lungs. Isolated thoracic lymph nodes cells from eNOS overexpressing mice that have been sensitized and challenged with ovalbumin produced significantly less of the cytokines IFN-γ, IL-5 and IL-10. No difference in serum IgE levels could be found. Further, there was a 50% reduction in the number of lymphocytes and eosinophils in the lung lavage fluid of these animals. Finally, airway hyperresponsiveness to methacholine was abolished in eNOS overexpressing mice. CONCLUSION: These findings demonstrate that eNOS overexpression attenuates both airway inflammation and airway hyperresponsiveness in a model of allergic asthma. We suggest that a delicate balance in the production of bioactive forms of NO derived from eNOS might be essential in the pathophysiology of asthma

Haematological effects of Bordetella pertussis components in rat and guinea pig: species differences

Effecten zijn bestudeerd van endotoxine en pertussis (PT) toxine geisoleerd uit Bordetella pertussis op het hematologische beeld van de rat en de cavia. PT vertoonde in de rat pas na een aantal dagen een sterke leucocytose t.g.v. een lymfocytose, een granulocytose en een monocytose. Een dergelijke leucocytose was niet waarneembaar in de cavia. Gesuggereerd wordt dat de afwezigheid van een door PT geinduceerde leucocytose in de cavia mogelijk gecorreleerd is aan de afwezigheid van farmacologische effecten van PT in deze species. Deze correlatie is bediscussieerd in termen van een verminderde bindingsaffiniteit van PT voor cellulaire structuren in de cavia. Endotoxine veroorzaakte in beide species, enkele uren na toediening, een significante leucocytopenie en in de rat tevens thrombocytopenie. In de cavia werd bovendien enkele dagen na toediening een significante toename van de lymfocytenconcentratie en een afname van de neutrofiele granulocytenconcentratie bij een gelijkblijvende leucocytenconcentratie waargenomen. Bediscussieerd wordt de mogelijke relatie van late endotoxine geinduceerde farmacologische effecten in de cavia en de mogelijke rol die neutrofiele granulocyten hierbij kunnen spelen.Abstract not availableGH

Intra-luminal exposure of murine airways to peroxynitrite causes inflammation but not hyperresponsiveness

Objective and design: There is increasing evidence for the involvement of reactive nitrogen species like peroxynitrite (ONOO-) in airway pathology, for example during allergic airway inflammation. Therefore, the effect of peroxynitrite exposure on airway responsiveness and inflammation was studied. Materials: Male BALB/c mice were treated intra-tracheally with authentic peroxynitrite and the peroxynitrite donor 3-morpholinosydnonimine (SIN-1). Control animals received decomposed solutions of peroxynitrite and SIN-1. Methods: Airway inflammation was monitored by broncho-alveolar lavage, three and seven days after administration. Airway responsiveness to methacholine and acetylcholine was measured on day 1, 2, 3 and 7 post administration using whole body plethysmography. Results: Intra-tracheal administration of peroxynitrite 200 muM in 50 mul phosphate buffered saline (PBS) induced a significant increase in macrophages (>35%, p <0.05) in the airway lumen three days after administration. In contrast, neither intra-tracheal administration of authentic peroxynitrite (up to 5 mM) nor the peroxynitrite donor SIN-1 (1 mM, both intra-tracheal and nebulized) changed airway responsiveness to methacholine. Moreover, peroxynitrite (5 mM) did not alter responsiveness to acetylcholine. Conclusion: Administration of peroxynitrite directly into the airways of BALB/c mice, induces airway inflammation, but not airway hyperresponsiveness. It is suggested that antioxidants in the epithelial lining fluid and/or the epithelium itself form an efficient barrier, which prevents peroxynitrite from reaching putative targets in the airway interstitium

Intra-luminal exposure of murine airways to peroxynitrite causes inflammation but not hyperresponsiveness

Objective and design: There is increasing evidence for the involvement of reactive nitrogen species like peroxynitrite (ONOO-) in airway pathology, for example during allergic airway inflammation. Therefore, the effect of peroxynitrite exposure on airway responsiveness and inflammation was studied. Materials: Male BALB/c mice were treated intra-tracheally with authentic peroxynitrite and the peroxynitrite donor 3-morpholinosydnonimine (SIN-1). Control animals received decomposed solutions of peroxynitrite and SIN-1. Methods: Airway inflammation was monitored by broncho-alveolar lavage, three and seven days after administration. Airway responsiveness to methacholine and acetylcholine was measured on day 1, 2, 3 and 7 post administration using whole body plethysmography. Results: Intra-tracheal administration of peroxynitrite 200 muM in 50 mul phosphate buffered saline (PBS) induced a significant increase in macrophages (>35%, p <0.05) in the airway lumen three days after administration. In contrast, neither intra-tracheal administration of authentic peroxynitrite (up to 5 mM) nor the peroxynitrite donor SIN-1 (1 mM, both intra-tracheal and nebulized) changed airway responsiveness to methacholine. Moreover, peroxynitrite (5 mM) did not alter responsiveness to acetylcholine. Conclusion: Administration of peroxynitrite directly into the airways of BALB/c mice, induces airway inflammation, but not airway hyperresponsiveness. It is suggested that antioxidants in the epithelial lining fluid and/or the epithelium itself form an efficient barrier, which prevents peroxynitrite from reaching putative targets in the airway interstitium

L-Arginine is not the limiting factor for nitric oxide synthesis by human alveolar macrophages in vitro

Unlike murine mononuclear phagocytes, human macrophages do not release high amounts of nitric oxide (NO) in vitro despite the presence of nitric oxide synthase (NOS). To determine whether this limited NO synthesis in vitro is due to limited availability of the NOS substrate L-arginine, and putative NOS inhibiting factors present in foetal serum preparations, both alveolar macrophages (AM) and monocyte derived macrophages (MDM) were incubated in various circumstances. Nitrite production measured using stimulated AM was typically It is concluded that the limited nitric oxide production of human macrophages in vitro can neither be explained by limited availability of L-arginine, nor by nitric oxide synthase inhibiting substances in foetal serum. Furthermore, it is shown that nitrite release from N omega -hydroxy-L-arginine by alveolar macrophages is nitric oxide synthase independent