Emphysema is characterized by loss of lung tissue elasticity and destruction of structures supporting alveoli and capillaries. The impact of mechanical ventilation strategies on ventilator-induced lung injury (VILI) in emphysema is poorly defined. New ventilator strategies should be developed to minimize VILI in emphysema. The present study was divided into two protocols: (1) characterization of an elastase-induced emphysema model in rats and identification of the time point of greatest cardiorespiratory impairment, defined as a high specific lung elastance associated with large right ventricular end-diastolic area; and (2) comparison between variable (VV) and conventional volume-controlled ventilation (VCV) on lung mechanics and morphometry, biological markers, and cardiac function at that time point. In the first protocol, Wistar rats (n = 62) received saline (SAL) or porcine pancreatic elastase (ELA) intratracheally once weekly for 4 weeks, respectively. Evaluations were performed 1, 3, 5, or 8 weeks after the last intratracheal instillation of saline or elastase. After identifying the time point of greatest cardiorespiratory impairment, an additional 32 Wistar rats were randomized into the SAL and ELA groups and then ventilated with VV or VCV (n = 8/group) [tidal volume (VT) = 6 mL/kg, positive end-expiratory pressure (PEEP) = 3 cmH2O, fraction of inspired oxygen (FiO2) = 0.4] for 2 h. VV was applied on a breath-to-breath basis as a sequence of randomly generated VT values (mean VT = 6 mL/kg), with a 30% coefficient of variation. Non-ventilated (NV) SAL and ELA animals were used for molecular biology analysis. The time point of greatest cardiorespiratory impairment, was observed 5 weeks after the last elastase instillation. At this time point, interleukin (IL)-6, cytokine-induced neutrophil chemoattractant (CINC)-1, amphiregulin, angiopoietin (Ang)-2, and vascular endothelial growth factor (VEGF) mRNA levels were higher in ELA compared to SAL. In ELA animals, VV reduced respiratory system elastance, alveolar collapse, and hyperinflation compared to VCV, without significant differences in gas exchange, but increased right ventricular diastolic area. Interleukin-6 mRNA expression was higher in VCV and VV than NV, while surfactant protein-D was increased in VV compared to NV. In conclusion, VV improved lung function and morphology and reduced VILI, but impaired right cardiac function in this model of elastase induced-emphysema.

Emphysema is an intractable pulmonary disease characterized by an inflammatory process of the airways and lung parenchyma and ongoing remodeling process in an attempt to restore lung structure. There is no effective drug therapy that regenerates lung tissue or prevents the progression of emphysema; current treatment is aimed at symptomatic relief. We hypothesized that LASSBio-596, a molecule with potent anti-inflammatory and immunomodulatory effects, might reduce pulmonary inflammation and remodeling and thus improve lung function in experimental emphysema. Emphysema was induced in BALB/c mice by intratracheal administration of porcine pancreatic elastase (0.1 IU) once weekly during 4 weeks. A control group received saline using the same protocol. After the last instillation of saline or elastase, dimethyl sulfoxide, or LASSBio-596 were administered intraperitoneally, once daily for 8 days. After 24 h, in elastase-induced emphysema animals, LASSBio-596 yielded: (1) decreased mean linear intercept, hyperinflation and collagen fiber content, (2) increased elastic fiber content, (3) reduced number of M1 macrophages, (4) decreased tumor necrosis factor-α, interleukin-1β, interleukin-6, and transforming growth factor-β protein levels in lung tissue, and increased vascular endothelial growth factor. These changes resulted in increased static lung elastance. In conclusion, LASSBio-596 therapy reduced lung inflammation, airspace enlargement, and small airway wall remodeling, thus improving lung function, in this animal model of elastase-induced emphysema.

Aim: We investigated the therapeutic effects of aerobic training on lung mechanics, inflammation, morphometry and biological markers associated with inflammation, and endothelial cell damage, as well as cardiac function in a model of elastase-induced emphysema.Methods: Eighty-four BALB/c mice were randomly allocated to receive saline (control, C) or 0.1 IU porcine pancreatic elastase (emphysema, ELA) intratracheally once weekly for 4 weeks. After the end of administration period, once cardiorespiratory impairment associated with emphysema was confirmed, each group was further randomized into sedentary (S) and trained (T) subgroups. Trained mice ran on a motorized treadmill, at moderate intensity, 30 min/day, 3 times/week for 4 weeks.Results: Four weeks after the first instillation, ELA animals, compared to C, showed: (1) reduced static lung elastance (Est,L) and levels of vascular endothelial growth factor (VEGF) in lung tissue, (2) increased elastic and collagen fiber content, dynamic elastance (E, in vitro), alveolar hyperinflation, and levels of interleukin-1β and tumor necrosis factor (TNF)-α, and (3) increased right ventricular diastolic area (RVA). Four weeks after aerobic training, ELA-T group, compared to ELA-S, was associated with reduced lung hyperinflation, elastic and collagen fiber content, TNF-α levels, and RVA, as well as increased Est,L, E, and levels of VEGF.Conclusion: Four weeks of regular and moderate intensity aerobic training modulated lung inflammation and remodeling, thus improving pulmonary function, and reduced RVA and pulmonary arterial hypertension in this animal model of elastase-induced emphysema.

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.

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.