Prm Rocco

Angiotensin‐(1‐7) attenuates airway remodelling and hyperresponsiveness in a model of chronic allergic lung inflammation

A long‐term imbalance between pro‐ and anti‐inflammatory mediators leads to airway remodelling, which is strongly correlated to most of the symptoms, severity and progression of chronic lung inflammation. The Angiotensin‐(1‐7) [Ang‐(1‐7)]/Mas receptor axis of the renin‐angiotensin system is associated with attenuation of acute and chronic inflammatory processes. In this study, we investigated the effects of Ang‐(1‐7) treatment in a model of chronic allergic lung inflammation.

Comparison of different degrees of variability in tidal volume to prevent deterioration of respiratory system elastance in experimental acute lung inflammation

BACKGROUND Variable ventilation improves respiratory function, but it is not known whether the amount of variability in tidal volume (VT) can be reduced in recruited lungs without a deterioration of respiratory system elastance. METHODS Acute lung inflammation was induced by intratracheal instillation of lipopolysaccharide in 35 Wistar rats. Twenty-eight animals were anaesthetized and ventilated in volume-controlled mode. Lungs were recruited by random variation of VT (mean 6 ml kg(-1), coefficient of variation 30%, normal distribution) for 30 min. Animals were randomly assigned to different amounts of VT variability (n=7 for 90 min per group): 30, 15, 7.5, or 0%. Lung function, diffuse alveolar damage, and gene expression of biological markers associated with cell mechanical stress, inflammation, and fibrogenesis were assessed. Seven animals were not ventilated and served as controls for post-mortem analyses. RESULTS A VT variability of 30%, but not 15, 7.5, or 0%, prevented deterioration of respiratory system elastance [Mean (SD) -7.5 (8.7%), P<0.05; 21.1 (9.6%), P<0.05; 43.3 (25.9), P<0.05; and 41.2 (16.4), P<0.05, respectively]. Diffuse alveolar damage was lower with a VT variability of 30% than with 0% and without ventilation, because of reduced oedema and haemorrhage. A VT variability of 30, 15, or 7.5% reduced the gene expression of amphiregulin, cytokine-induced neutrophil chemoattractant-1, and tumour necrosis factor α compared with a VT variability of 0%. CONCLUSIONS In this model of acute lung inflammation, a VT variability of 30%, compared with 15 and 7.5%, was necessary to avoid deterioration of respiratory system elastance and was not associated with lung histological damage.

The tyrosine kinase inhibitor dasatinib reduces lung inflammation and remodelling in experimental allergic asthma

Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in understanding of its pathophysiology, asthma remains a major public health problem, and new therapeutic strategies are urgently needed. In this context, we sought to ascertain whether treatment with the TK inhibitor dasatinib might repair inflammatory and remodelling processes, thus improving lung function, in a murine model of asthma.

Effects of acute hypercapnia with and without acidosis on lung inflammation and apoptosis in experimental acute lung injury

We investigated the effects of acute hypercapnic acidosis and buffered hypercapnia on lung inflammation and apoptosis in experimental acute lung injury (ALI). Twenty-four hours after paraquat injection, 28 Wistar rats were randomized into four groups (n=7/group): (1) normocapnia (NC, PaCO2=35-45 mmHg), ventilated with 0.03%CO2+21%O2+balancedN2; (2) hypercapnic acidosis (HC, PaCO2=60-70 mmHg), ventilated with 5%CO2+21%O2+balancedN2; and (3) buffered hypercapnic acidosis (BHC), ventilated with 5%CO2+21%O2+balancedN2 and treated with sodium bicarbonate (8.4%). The remaining seven animals were not mechanically ventilated (NV). The mRNA expression of interleukin (IL)-6 (p=0.003), IL-1β (p<0.001), and type III procollagen (PCIII) (p=0.001) in lung tissue was more reduced in the HC group in comparison with NC, with no significant differences between HC and BHC. Lung and kidney cell apoptosis was reduced in HC and BHC in comparison with NC and NV. In conclusion, in this experimental ALI model, hypercapnia, regardless of acidosis, reduced lung inflammation and lung and kidney cell apoptosis.

Effects of inhalational anaesthetics in experimental allergic asthma.

We evaluated whether isoflurane, halothane and sevoflurane attenuate the inflammatory response and improve lung morphofunction in experimental asthma. Fifty‐six BALB/c mice were sensitised and challenged with ovalbumin and anaesthetised with isoflurane, halothane, sevoflurane or pentobarbital sodium for one hour. Lung mechanics and histology were evaluated. Gene expression of pro‐inflammatory (tumour necrosis factor‐α), pro‐fibrogenic (transforming growth factor‐β) and pro‐angiogenic (vascular endothelial growth factor) mediators, as well as oxidative process modulators, were analysed. These modulators included nuclear factor erythroid‐2 related factor 2, sirtuin, catalase and glutathione peroxidase. Isoflurane, halothane and sevoflurane reduced airway resistance, static lung elastance and atelectasis when compared with pentobarbital sodium. Sevoflurane minimised bronchoconstriction and cell infiltration, and decreased tumour necrosis factor‐α, transforming growth factor‐β, vascular endothelial growth factor, sirtuin, catalase and glutathione peroxidase, while increasing nuclear factor erythroid‐2‐related factor 2 expression. Sevoflurane down‐regulated inflammatory, fibrogenic and angiogenic mediators, and modulated oxidant–antioxidant imbalance, improving lung function in this model of asthma.

Regular and moderate aerobic training before allergic asthma induction reduces lung inflammation and remodeling

Experimental studies have reported that aerobic exercise after asthma induction reduces lung inflammation and remodeling. Nevertheless, no experimental study has analyzed whether regular/moderate aerobic training before the induction of allergic asthma may prevent these inflammatory and remodeling processes. For this purpose, BALB/c mice (n = 96) were assigned into non‐trained and trained groups. Trained animals ran on a motorized treadmill at moderate intensity, 30 min/day, 3 times/week, for 8 weeks, and were further randomized into subgroups to undergo ovalbumin sensitization and challenge or receive saline using the same protocol. Aerobic training continued until the last challenge. Twenty‐four hours after challenge, compared to non‐trained animals, trained mice exhibited: (a) increased systolic output and left ventricular mass on echocardiography; (b) improved lung mechanics; (c) decreased smooth muscle actin expression and collagen fiber content in airways and lung parenchyma; (d) decreased transforming growth factor (TGF)‐β levels in bronchoalveolar lavage fluid (BALF) and blood; (e) increased interferon (IFN)‐γ in BALF and interleukin (IL)‐10 in blood; and (f) decreased IL‐4 and IL‐13 in BALF. In conclusion, regular/moderate aerobic training prior to allergic asthma induction reduced inflammation and remodeling, perhaps through increased IL‐10 and IFN‐γ in tandem with decreased Th2 cytokines.

Effects of pressure control and pressure support ventilation on ventilator induced lung injury in experimental acute respiratory distress syndrome with intra-abdominal hypertension

In acute respiratory distress syndrome (ARDS), intra-abdominal hypertension (IAH) increases intra-thoracic pressures, leading atelectasis and deterioration of respiratory mechanics and gas-exchange. The optimal setting of mechanical ventilation (MV) and its impact on respiratory function and ventilator-induced lung injury (VILI) in ARDS associated with IAH needs to be better clarified. Lung-protective MV with low tidal volume (VT) and positive end-expiratory pressure (PEEP) has been recommended; however, assisted MV may be a favorable alternative to controlled MV at the early phase of ARDS, since it requires less sedation, no paralysis and is associated with better lung protection, reducing the risk of VILI. We hypothesized that pressure-support ventilation (PSV) improve pulmonary morphofunction and minimize lung injury in ARDS with IAH.

Cellular response to mechanical stress

Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a common severe inflammatory disease of the lungs and has a mortality rate of at least 30% [[1]–[4]. Mechanical ventilation is a critical component of the treatment of patients with ARDS and is often lifesaving for these patients. However, its improper use can worsen, or even cause lung injury, in a condition referred to as ventilator-induced lung injury (VILI).

Distensibility index of the inferior vena cava in experimental acute respiratory distress syndrome.

We determined the accuracy of distensibility index of inferior vena cava (dIVC) for evaluation of fluid responsiveness in rats with acute respiratory distress syndrome (ARDS) and validated this index for use in rat models. In protocol 1, E. coli lipopolysaccharide was administered in Wistar rats (n=7). After 24h, animals were mechanically ventilated, and stroke volume (SV) and dIVC quantified after blood drainage and subsequent volume expansion (albumin 20%). A receiver operating characteristic (ROC) curve was plotted to determine the optimal dIVC cutoff. In protocol 2, rats (n=10) were divided into fluid-responders (SV increase >5%) and nonresponders (SV increase <5%). The dIVC cutoff obtained from protocol 1 was 25%. Fluid responders had a 2.5 relative risk of low dIVC (<25%). The sensitivity, specificity, positive predictive, and negative predictive values for dIVC were 74%, 62%, 59%, and 76%, respectively. In conclusion, a dIVC threshold <25% was associated with positive response after volume expansion and could be used to titrate fluids in endotoxin-induced ARDS.

Effects of pressure-support ventilation with different levels of positive end-expiratory in a mild model of acute respiratory distress syndrome

Pressure-support ventilation improves lung mechanics, blood gas exchange, hemodynamics, and work of breathing (WOB) in mild acute respiratory distress syndrome (ARDS) [1, 2]. Nevertheless, those beneficial effects could be dependent of positive end-expiratory pressure (PEEP) applied during mechanical ventilation. So far, no study has compared pressure-support ventilation (PSV) with pressure controlled ventilation (PCV) in different PEEP levels.