In experimental elastase-induced emphysema, mechanical ventilation with variable tidal volumes (V_T) set to 30% coefficient of variation (CV) may result in more homogenous ventilation distribution, but might also impair right heart function. We hypothesized that a different CV setting could improve both lung and cardiovascular function. Therefore, we investigated the effects of different levels of V_T variability on cardiorespiratory function, lung histology, and gene expression of biomarkers associated with inflammation, fibrogenesis, epithelial cell damage, and mechanical cell stress in this emphysema model. Wistar rats (n = 35) received repeated intratracheal instillation of porcine pancreatic elastase to induce emphysema. Seven animals were not ventilated and served as controls (NV). Twenty-eight animals were anesthetized and assigned to mechanical ventilation with a V_T CV of 0% (BASELINE). After data collection, animals (n = 7/group) were randomly allocated to V_T CVs of 0% (VV₀); 15% (VV₁₅); 22.5% (VV_22.5); or 30% (VV₃₀). In all groups, mean V_T was 6 mL/kg and positive end-expiratory pressure was 3 cmH₂O. Respiratory system mechanics and cardiac function (by echocardiography) were assessed continuously for 2 h (END). Lung histology and molecular biology were measured post-mortem. VV_22.5 and VV₃₀ decreased respiratory system elastance, while VV₁₅ had no effect. VV₀, VV₁₅, and VV_22.5, but not VV₃₀, increased pulmonary acceleration time to pulmonary ejection time ratio. VV_22.5 decreased the central moment of the mean linear intercept (D2 of Lm) while increasing the homogeneity index (1/β) compared to NV (77 ± 8 μm vs. 152 ± 45 μm; 0.85 ± 0.06 vs. 0.66 ± 0.13, p < 0.05 for both). Compared to NV, VV₃₀ was associated with higher interleukin-6 expression. Cytokine-induced neutrophil chemoattractant-1 expression was higher in all groups, except VV_22.5, compared to NV. IL-1β expression was lower in VV_22.5 and VV₃₀ compared to VV₀. IL-10 expression was higher in VV_22.5 than NV. Club cell protein 16 expression was higher in VV_22.5 than VV₀. SP-D expression was higher in VV₃₀ than NV, while SP-C was higher in VV₃₀ and VV_22.5 than VV_0. In conclusion, VV_22.5 improved respiratory system elastance and homogeneity of airspace enlargement, mitigated inflammation and epithelial cell damage, while avoiding impairment of right cardiac function in experimental elastase-induced emphysema.

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