Acidosis Stimulates Nitric Oxide Production and Lung Damage in Rats

Pedoto, Alessia; Caruso, Jennifer; Nandi, Jyotirmoy; Oler, Albert; Hoffmann, Stephen; Tassiopoulos, Apostolos K.; McGraw, Daniel J.; Camporesi, Enrico M.; Hakim, T. S.

doi:10.1164/ajrccm.159.2.9802093

Cited by 136 publications

(95 citation statements)

References 34 publications

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“…However, the paradox in which mild and severe acidosis induced by HCl results in opposite effects on NO has not been satisfactorily explained. Pedoto and colleagues (29) suggested that the optimal intracellular pH (pH i ) for iNOS is near 7.0 and that the addition of acid would lower pH i toward the optimal value, thus increasing iNOS activity and NO production. Further addition of acid would cause pH i to fall below the optimal value, leading to a decrease in NO production (29).…”

Section: Discussionmentioning

confidence: 99%

“…Pedoto and colleagues (29) suggested that the optimal intracellular pH (pH i ) for iNOS is near 7.0 and that the addition of acid would lower pH i toward the optimal value, thus increasing iNOS activity and NO production. Further addition of acid would cause pH i to fall below the optimal value, leading to a decrease in NO production (29). This hypothesis was recently tested by Huang et al (14), who demonstrated that the optimal pH o for NO formation by iNOS was 7.2 in RAW 264.7 cells.…”

Section: Discussionmentioning

confidence: 99%

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Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells

Kellum

Song

2004

American Journal of Physiology-Regulatory, Integrative and Comp

192

122

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Metabolic acidosis frequently complicates sepsis and septic shock and may be deleterious to cellular function. Different types of metabolic acidosis (e.g., hyperchloremic and lactic acidosis) have been associated with different effects on the immune response, but direct comparative studies are lacking. Murine macrophage-like RAW 264.7 cells were cultured in complete medium with lactic acid or HCl to adjust the pH between 6.5 and 7.4 and then stimulated with LPS ( Escherichia coli 0111:B4; 10 ng/ml). Nitric oxide (NO), IL-6, and IL-10 levels were measured in the supernatants. RNA was extracted from the cell pellets, and RT-PCR was performed to amplify corresponding mediators. Gel shift assay was also performed to assess NF-κB DNA binding. Increasing concentrations of acid caused increasing acidification of the media. Trypan blue exclusion and lactate dehydrogenase release demonstrated that acidification did not reduce cell viability. HCl significantly increased LPS-induced NO release and NF-κB DNA binding at pH 7.0 but not at pH 6.5. IL-6 and IL-10 expression (RNA and protein) were reduced with HCl-induced acidification, but IL-10 was reduced much more than IL-6 at low pH. By contrast, lactic acid significantly decreased LPS-induced NO, IL-6, and IL-10 expression in a dose-dependent manner. Lactic acid also inhibited LPS-induced NF-κB DNA binding. Two common forms of metabolic acidosis (hyperchloremic and lactic acidosis) are associated with dramatically different patterns of immune response in LPS-stimulated RAW 264.7 cells. HCl is essentially proinflammatory as assessed by NO release, IL-6-to-IL-10 ratios, and NF-κB DNA binding. By contrast, lactic acidosis is anti-inflammatory.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells

Kellum

Song

2004

American Journal of Physiology-Regulatory, Integrative and Comp

192

122

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“…Lung MPO was assessed as an index of PMN numbers (30). Briefly, whole unlavaged lungs were homogenized in 2 ml of 50 mM KH 2 PO 4 , pH 7.4, and centrifuged, and the supernatant was discarded.…”

Section: Methodsmentioning

confidence: 99%

Cyclophosphamide Decreases Nitrotyrosine Formation and Inhibits Nitric Oxide Production by Alveolar Macrophages in Mycoplasmosis

Hickman-Davis¹,

Lindsey

Matalon

2001

Infect Immun

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We previously reported that congenic C57BL/6 inducible nitric oxide synthase ؊/؊ (iNOS ؊/؊ ) mice infected with Mycoplasma pulmonis developed higher bacterial numbers and lung lesion scores than C57BL/6 iNOS Mycoplasma pneumoniae accounts for 20 to 25% of pneumonias in all age groups, causes tracheobronchitis with prolonged pulmonary clearance and airway hyperresponsiveness, and may contribute to initiation and persistence of asthma. In addition, studies have shown that 46% of M. pneumoniae infections are misdiagnosed and that 10% of the patients correctly diagnosed with this illness are treated inappropriately (5). Host defense mechanisms against mycoplasmas are poorly characterized. However, studies with animal models have demonstrated that innate immunity is extremely important for the control and clearance of pulmonary mycoplasmal infections (20).Mycoplasma pulmonis infection in mice is the best available model for human respiratory mycoplasmosis. M. pulmonis causes a suppurative pneumonia in which infection and disease spread centrifugally in the respiratory tract resulting in the presence of cellular exudates in alveoli indicative of maximum disease severity (4). The airway exudate consists primarily of polymorphonuclear cells (PMNs), while the alveolar exudate is mixed PMNs and macrophages. In the absence of a specific antibody, PMNs are unable to clear mycoplasmas and appear to contribute more to pathology than to the resolution of disease. Activated PMNs secrete a number of proteases, including elastase and myeloperoxidase (MPO), as well as reactive oxygen-nitrogen species including nitric oxide (NO ⅐ ), superoxide (O 2 .Ϫ ), and hydrogen peroxide (H 2 O 2 ), which alone or in combination may damage the pulmonary epithelium. Our studies of host defense mechanisms against mycoplasmas have identified the alveolar macrophage (AM) as the primary effector cell in early mycoplasmal clearance (20). Activated AMs also produce NO ⅐ via inducible nitric oxide synthase (iNOS) and O 2 .Ϫ via NADPH oxidase. Interaction of NO ⅐ with O 2

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“…In fact, exhaled NO was significantly correlated with carbon monoxide diffusing capacity of the lungs (DL,CO) and was independent of inhaled corticosteroid therapy [118]. Acidosis is frequently associated with exacerbations of COPD and may have a direct vasodilatory influence on the systemic vasculature, and lead to increased NO production, and myeloperoxidase activity in lung [119]. In fact, in an acidic environment, the reaction between NO and oxygen radicals becomes further enhanced, leading to more tissue damage [120].…”

Section: Chronic Obstructive Pulmonary Diseasementioning

confidence: 99%

Clinical aspects of exhaled nitric oxide

2000

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There has been intense research into the role nitric oxide (NO) plays in physiological and pathological mechanisms and its clinical significance in respiratory medicine.Elevated levels of exhaled levels of exhaled NO in asthma and other inflammatory lung diseases lead to many studies examining NO as potential markers of airway inflammation, enabling repeated noninvasive and standardized monitoring of airway inflammation. In airway inflammation, NO is not merely a marker but may have antiinflammatory and pro-inflammatory effects. Significant correlation has been found between exhaled NO and skin test scores in steroid naive asthmatic patients, allowing to discriminate patients with and without airway responsiveness. Exhaled NO is significantly elevated in acute asthma, or steroid-resistant severe asthma, or when the maintenance dose of inhaled steroids is reduced, and quickly reduced down to the levels in patients with stable asthma after steroid treatment. Exhaled NO has been successfully used to monitor anti-inflammatory treatment with inhaled corticosteroids in asthma. Exhaled NO is extremely sensitive and rapid marker of the dose-dependent effect of steroid treatment, or asthma deterioration, which is increased to any changes in lung function, provocative concentration causing a 20% fall in forced expiratory volume, sputum eosinophilia or asthma symptoms. Exhaled NO is not increased in stable chronic obstructive pulmonary disease (COPD), but patients with unstable COPD, or bronchiectasis have high NO levels. Exhaled and nasal NO are diagnostically low in cystic fibrosis and primary pulmonary dyskinesia.Analysis of exhaled air, including nitric oxide, is feasible and could provide a noninvasive method for use in monitoring and management of lung diseases. Eur Respir J 2000; 16: 781±792.

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Acidosis Stimulates Nitric Oxide Production and Lung Damage in Rats

Cited by 136 publications

References 34 publications

Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells

Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells

Cyclophosphamide Decreases Nitrotyrosine Formation and Inhibits Nitric Oxide Production by Alveolar Macrophages in Mycoplasmosis

Clinical aspects of exhaled nitric oxide

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