IL expression was higher in VV Club cell protein 16 expression was higher in VV In conclusion, VV Noninvasive ventilation is widely used in COPD patients and is associated with shorter length of hospital stay, lower mortality rates, and lower costs as compared to invasive methods Lindenauer et al.
On the other hand, patients with more severe disease may still require invasive mechanical ventilation Stefan et al. In volume-controlled mechanical ventilation, due to its inherent monotonous pattern, the amplitude and duration of inflation and deflation are comparable. This, taking into account the time-constant inhomogeneity observed in COPD, can lead to delayed inflation of some lung areas and overdistension in others Laghi et al.
This scenario may predispose to the development of ventilator-induced lung injury VILI , further increasing the impedance of the pulmonary vascular bed and worsening the impact of mechanical ventilation on right ventricular RV function, which is already impaired in COPD Vieillard-Baron et al.
Variable ventilation VV , which is characterized by breath-to-breath variation of tidal volume V T , has been shown to improve oxygenation Lefevre et al. Such beneficial effects have been ascribed to the potential of VV to recruit the lungs Ruth Graham et al. Importantly, VV also improves distribution of ventilation across lung areas with different time constants Huhle et al.
In theory, since emphysema and acute lung injury present distinct lung structural and functional changes, we hypothesized that a different setting of CV could improve both lung and cardiovascular function in experimental elastase-induced emphysema.
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The time course of interventions is depicted in Figure 1. Five weeks after the last instillation, experiments were performed. Figure 1. Design and timeline of experiments. Seven animals were non-ventilated NV , serving as a control group. Braun, Crissier, Switzerland. Body temperature was maintained at At the end of the experiment END , echocardiographic parameters, respiratory system mechanics, and arterial blood gases were analyzed.
Shaved animals were placed in the dorsal recumbent position. Images were obtained from the subcostal and parasternal views. Short-axis two-dimensional views were acquired at the level of the papillary muscles to measure LV and RV areas. E and R were calculated offline based on the equation of motion Uhlig et al. Immediately after removal, the left lung was flash-frozen by immersion in liquid nitrogen, fixed with Carnoy's solution, and paraffin-embedded.
An investigator MSC blinded to the origin of the material performed the microscopic examination.
Morphometric analysis was done using an integrating eyepiece with a coherent system made of a point grid, consisting of 50 lines of known length, coupled to a conventional light microscope Axioplan, Zeiss, Oberkochen, Germany. To characterize the heterogeneity of airspace enlargement, the central moment of the mean linear intercept D 2 of Lm was computed from 20 airspace measurements Parameswaran et al. The primers used are described in the online supplement Table S1. Samples were run in triplicate. Effect-size estimates were based on a previous study using the elastase instillation model of emphysema.
Molecular biology variables were compared using the Kruskal—Wallis test followed by Dunn's multiple comparisons. All tests were performed in GraphPad Prism v6. Table 1. Figure 2.
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Cardiovascular function was assessed by echocardiography. Data presented as mean and standard deviation of 7 animals in all groups. Lower panel: representative images of pulmonary blood flow. Figure 3 depicts light microscopy images of one representative animal per group. Morphometric data are shown in Table 3. Figure 3. Representative light microscopy images.
CC16 expression was higher in VV Figure 4. Data are presented as a box plot. Lines denote the median and boxes delimit the 25th and 75th percentiles of 7 animals per group. Relative gene expression was calculated as a ratio of the average gene expression levels compared with the reference gene 36B4 and expressed as fold change relative to NV. Figure 5.
Table 4. The main findings of the present study were that, in a rat model of experimental emphysema: VV To the best of our knowledge, this was the first investigation of the effects of different levels of V T variability on pulmonary and cardiovascular function, lung morphometry, and gene expression of markers of inflammation, surfactant proteins, epithelial cell damage, cell mechanical stress, and fibrogenesis in experimental emphysema.
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We chose the repeated intratracheal elastase instillation model because it reproduces important features of emphysema, including deterioration of respiratory system mechanics, airspace enlargement, and lung inflammation Antunes and Rocco, ; Cruz et al. Furthermore, multiple elastase instillations can lead to cardiorespiratory alterations Antunes et al. We chose to conduct analyses 5 weeks after the last elastase instillation because this time point provides an adequate combination of cardiorespiratory function impairment and structural lung damage Henriques et al.
The levels of V T variability were selected on the basis of our previous experience with variable ventilation in models of acute lung injury Spieth et al. Our finding that VV improved E is in agreement with studies in models of acute lung injury Thammanomai et al. VV is able to recruit the lungs more efficiently than conventional recruitment maneuvers Thammanomai et al. In this line, Thammanomai et al. In emphysema, a substantial degree of small airway narrowing can be present McDonough et al. In addition, the fact that VV applies subphysiological V T values may have helped limit hyperinflation during mechanical ventilation and promote emptying of lung regions with lower time constants.
Although we did not observe differences in overall resistance, we cannot exclude that regional resistance might have been affected by tissue destruction Hantos et al. It is worth noting that elastance improved continuously with increasing variability in V T , and was lowest at VV Curiously, this behavior is similar to that described during VV in experimental acute lung injury Spieth et al. Up to this V T level, we were likely still located on the linear portion of the respiratory system pressure—volume curve Ito et al. Our data also suggest that the improvement in elastance might be related to an increase in surfactant production.
Release of surfactant is known to be models Bartolak-Suki et al. Although we did not evaluate the cellular mechanisms of surfactant production in detail, mechanical stretch has been shown to stimulate surfactant production through epidermal growth factor receptor EGFR phosphorylation Sanchez-Esteban et al. In addition, one possible explanation for the increase in surfactant mRNA synthesis would be improvement in overall cell bioenergetics.
In this context, variable stretch has been shown to improve ATP production by promoting mitochondrial biogenesis, which, in turn, led to structural changes such as increased organization of the actin, microtubule, and mitochondrial networks, as characterized by their fractal dimension and coefficient of variation Bartolak-Suki et al. By promoting cytoskeleton organization, the alveolar epithelial cells are more prone to start or continue surfactant synthesis into the alveolar space Singh et al.
Interestingly, oxygenation increased in all groups but was not further improved by VV, suggesting that a time-dependent recruitment effect occurred. This is likely explained by the use of PEEP in all groups. Furthermore, we cannot exclude the possibility that redistribution of perfusion without significant degrees of recruitment was present.
In fact, VV has been shown to improve oxygenation even when the fraction of non-aerated lung tissue increases Gama de Abreu et al. In agreement with a previous study from our group Henriques et al. Taken together, the findings of these studies indicate that higher V T variability impairs right heart function. The present study, however, adds to the present state of knowledge. Intermediate levels of variability, namely VV 15 and VV One possible explanation for this behavior is that both excessive and insufficient lung-unit recruitment, which have been observed at extremes of V T variability, led to high or low lung volumes respectively, thus increasing pulmonary vascular resistance Simmons, This hypothesis is supported by our observation that an intermediate-to-high level of variability, namely VV In addition to opening the lungs and keeping them homogeneously opened, VV Differences in the behaviors of these pro-inflammatory mediators may be associated with the pathophysiology of emphysema and with differential cell activation during VILI.
Interestingly, despite improvement in respiratory system mechanics, gene expression of IL-6 was increased at VV Importantly, variable ventilation did not result in increased cell mechanical stress or fibrogenesis, as indicated by amphiregulin and PCIII gene expressions, respectively. Nevertheless, VV CC16 is synthesized predominantly in the lungs, but also found in the circulation.
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Serum CC16 has been reported to decrease with lung disease progression Vestbo et al. In the present study, VV Our data suggest that, in patients with emphysema who require invasive mechanical ventilation, variation in tidal volumes may contribute to improved E and reduce the inhomogeneity of airspace enlargement, especially if a V T CV of This variability level can also reduce the likely negative impact of variable ventilation on right heart function without increasing the pro-inflammatory and pro-fibrotic lung response.
Clinical studies are necessary to determine the potential role of variable ventilation within this CV range in emphysema. This study has several limitations. First, the emphysema model used herein repeated intratracheal instillation of elastase does not entirely reproduce the clinical picture seen in humans, and cannot be directly extended to other models of emphysema. Second, the mechanical ventilation period 2 h was short. Long-term variable ventilation may lead to different results on analysis of inflammatory cell infiltration in lung tissue.
Third, since we tested only four levels of variability, we cannot exclude the possibility that intermediate levels might lead to different results.
Fourth, echocardiography was not gated by respiratory cycles, which may have affected measurement of cardiac function parameters. Nevertheless, the possibility of bias was minimized by the min imaging periods. Fifth, although there are several forms of tidal volume distribution, we chose a Gaussian distribution for technical reasons, local settings, and experience de Magalhaes et al.
For experts in the field of lung disease, it would be interesting to compare different distributions in order to extract the best readout in terms of cardiorespiratory interaction among them. Sixty, gene expression of biomarkers does not necessarily translate to increased protein levels; however, the relatively short period of intervention precluded protein analysis. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We express our gratitude to Mr. Andre Benedito da Silva for animal care, Mrs. Arlete Fernandes for her help with microscopy, Mrs. Moira Elizabeth Schottler and Mr. Filippe Vasconcellos for their assistance in editing the manuscript. Antunes, M. Effects of different mesenchymal stromal cell sources and delivery routes in experimental emphysema.