Variability in Tidal Volume Affects Lung and Cardiovascular Function Differentially in a Rat Model of Experimental Emphysema

Abstract

In experimental elastase-induced emphysema, mechanical ventilation with variable tidal volumes (VT) 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 VT 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 VT CV of 0% (BASELINE). After data collection, animals (n = 7/group) were randomly allocated to VT CVs of 0% (VV0); 15% (VV15); 22.5% (VV22.5); or 30% (VV30). In all groups, mean VT 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. VV22.5 and VV30 decreased respiratory system elastance, while VV15 had no effect. VV0, VV15, and VV22.5, but not VV30, increased pulmonary acceleration time to pulmonary ejection time ratio. VV22.5 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 VV22.5, compared to NV. IL-1β expression was lower in VV22.5 and VV30 compared to VV0. IL-10 expression was higher in VV22.5 than NV. Club cell protein 16 expression was higher in VV22.5 than VV0. SP-D expression was higher in VV30 than NV, while SP-C was higher in VV30 and VV22.5 than VV0. In conclusion, VV22.5 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.

Endotoxin-Induced Emphysema Exacerbation: A Novel Model of Chronic Obstructive Pulmonary Disease Exacerbations Causing Cardiopulmonary Impairment and Diaphragm Dysfunction

“…In the experimental model used herein, emphysema was induced by multiple instillations of PPE (Henriques et al, 2016; Padilha et al, 2016; Wierzchon et al, 2017). This model does not employ the primary disease-causing agent of COPD in humans, which is cigarette smoke.…”

“…Twenty-four Wistar rats (weight 442 ± 12 g) were randomly assigned into one of two groups: control (C) and emphysema (ELA). Emphysema was induced according to a protocol previously established by our team (Henriques et al, 2016; Wierzchon et al, 2017). Briefly, animals received four intratracheal instillations of pancreatic porcine elastase (PPE, 2 IU in 0.1 ml of saline solution, Sigma Chemical Co., St. Louis, MO, USA) at 1-week intervals (8 IU PPE in total).…”

“…where μ is the mean, σ is the variance of airspace diameters, and γ is the skewness of the diameter distribution. After D 2 calculation, the heterogeneity index ( β ) was derived from Lm and D 2 values by their ratio (Wierzchon et al, 2017).…”

“…The number of animals per group was based on previous studies from our laboratory (Henriques et al, 2016; Wierzchon et al, 2017). A sample size of six animals per group (providing for one animal as dropout) would provide the appropriate power (1 − β = 0.8) to identify significant ( α = 0.05) differences between C and ELA animals, taking into account an effect size d = 2.21, a two-sided test, and a sample size ratio = 1 (G * Power 3.1.9.2, University of Düsseldorf, Germany).…”

Effects of Protective Mechanical Ventilation With Different PEEP Levels on Alveolar Damage and Inflammation in a Model of Open Abdominal Surgery: A Randomized Study in Obese Versus Non-obese Rats

“…Lung morphometric analysis was performed using an integrating eyepiece with a coherent system consisting of a grid with 100 points and 50 lines of known length coupled to a conventional light microscope (Olympus BX51, Olympus Latin America Inc., São Paulo, Brazil). The volume fractions of the lung occupied by collapsed alveoli (alveoli with rough or plicate walls) and hyperinflated structures (alveolar ducts, alveolar sacs, or alveoli wider than 120 µm) were determined by the point-counting technique at a magnification of × 200 across 10 random, non-coincident microscopic fields (Hsia et al, 2010;Wierzchon et al, 2017).…”