Inducible Nitric Oxide Synthase Inhibition Attenuates Physical Stress-Induced Lung Hyper-Responsiveness and Oxidative Stress in Animals with Lung Inflammation

Abstract

Mechanisms involved in stress-induced asthmatic alterations have been poorly characterised. We assessed whether inducible nitric oxide synthase (iNOS) inhibition modulates the stress-amplified lung parenchyma responsiveness, oxidative stress and extracellular matrix remodelling that was previously increased by chronic lung inflammation. Guinea pigs were subjected to 7 exposures to ovalbumin (1–5 mg/ml) or saline (OVA and SAL groups) over 4 weeks. To induce behavioural stress, animals were subjected to a forced swimming protocol (5 times/week, over 2 weeks; SAL-Stress and OVA-Stress groups) 24 h after the 4th inhalation. 1400W (iNOS-specific inhibitor) was administered intraperitoneally in the last 4 days of the protocol (SAL-1400W, OVA-1400W, SAL-Stress+1400W and OVA-Stress+1400W groups). Seventy-two hours after the last inhalation, animals were anaesthetised and exsanguinated, and adrenal glands were removed. Lung tissue resistance and elastance were evaluated by oscillatory mechanics and submitted for histopathological evaluation. Stressed animals had higher adrenal weights compared to non-stressed groups, which were reduced by 1400W treatment. Behavioural stress in sensitised animals amplified the resistance and elastance responses after antigen challenge, numbers of eosinophils and iNOS+ cells, actin content and 8-iso-PGF2α density in the distal lung compared to the OVA group. 1400W treatment in ovalbumin-exposed and stressed animals reduced lung mechanics, iNOS+ cell numbers and 8-iso-PGF2α density compared to sensitised and stressed animals that received vehicle treatment. We concluded that stress amplifies the distal lung constriction, eosinophilic inflammation, iNOS expression, actin content and oxidative stress previously induced by chronic lung inflammation. iNOS-derived NO contributes to stress-augmented lung tissue functional alterations in this animal model and is at least partially due to activation of the oxidative stress pathway.

Eosinophilic Inflammation in Allergic Asthma

“…Even stress may amplify the eosinophilic infiltration in both airways and lung parenchyma among animals with allergic inflammation via immune response, demonstrating that these cells probably contribute to asthmatic response related to stress (Leick et al, 2012; Marques et al, 2012). It is well known that some modulators of the stress response have different effects on eosinophil recruitment (Nittoh et al, 1998; Machida et al, 2005), but is important to note that the complexity of these interactions still needs better clarifying.…”

“…Guinea pigs chronically exposed to OVA present an inflammatory response predominantly eosinophilic, showing a significant increase in eosinophil amount in airways, pulmonary parenchyma, and bronchoalveolar lavage (BAL), constituting an interesting experimental model to evaluate the participation of eosinophils in allergic inflammation (Tibério et al, 1997; Leick-Maldonado et al, 2004; Prado et al, 2005a,b; Lancas et al, 2006; Angeli et al, 2008; Nakashima et al, 2008; Ruiz-Schütz et al, 2009; Leick et al, 2012; Marques et al, 2012; Possa et al, 2012). …”

The effects of prenatal “psychological” stressor exposure on lung inflammation and hyperresponsiveness in adult rat offspring

“…Hyper‐responsiveness is a feature of the asthmatic rats that represents functional changes in their airway resistance and lung elasticity (Park et al, ). Measures of airway resistance and lung elasticity are commonly used in experiments to evaluate hyper‐responsiveness in respiratory disease models, including models with stress associations (Abreu et al, ; Almeida‐Reis et al, ; Marques et al, ).…”

Anti-IL17 na modulação da mecânica pulmonar, inflamação, estresse oxidativo e remodelamento da matriz extracelular em camundongos com inflamação pulmonar alérgica crônica exarcebada pelo LPS

“…Vários estudos de nosso grupo de pesquisa já demonstraram associação entre inflamação pulmonar alérgica crônica e aumento de óxido nítrico exalado e da expressão de iNOS (tanto em vais aéreas quanto parênquima pulmonar) no modelo de asma experimental em cobaias (Angeli et Nakashima et al, 2008;Ruiz-Schütz et al, 2008;Starling et al, 2009;Prado et al, 2011;Marques et al, 2012;Possa et al, 2012). O NO pode também ser convertido em nitrato, capaz de oxidar proteínas e contribuir para o estresse oxidativo, Isto pode ocorrer por intermédio da nitração da tirosina, em uma reação catalizada pela peroxidase eosinofílica (Wu et al, 1998). Elevados níveis de nitrotirosina foram observados em asmáticos (Hanazawa et al, 2000 de nitrogênio), que são produzidas pelos asmáticos podem exceder as defesas antioxidantes e causar estresse oxidativo (Hanazawa et al, 2000).…”