Gradually Increasing Tidal Volume May Mitigate Experimental Lung Injury in Rats

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: This study hypothesized that, in experimental mild acute respiratory distress syndrome, lung damage caused by high tidal volume (VT) could be attenuated if VT increased slowly enough to progressively reduce mechanical heterogeneity and to allow the epithelial and endothelial cells, as well as the extracellular matrix of the lung to adapt. For this purpose, different strategies of approaching maximal VT were tested. METHODS: Sixty-four Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24\u2009h, animals were randomly assigned to receive mechanical ventilation with VT = 6\u2009ml/kg for 2\u2009h (control); VT = 6\u2009ml/kg during hour 1 followed by an abrupt increase to VT = 22\u2009ml/kg during hour 2 (no adaptation time); VT = 6\u2009ml/kg during the first 30\u2009min followed by a gradual VT increase up to 22\u2009ml/kg for 30\u2009min, then constant VT = 22\u2009ml/kg during hour 2 (shorter adaptation time); and a more gradual VT increase, from 6 to 22\u2009ml/kg during hour 1 followed by VT = 22\u2009ml/kg during hour 2 (longer adaptation time). All animals were ventilated with positive end-expiratory pressure of 3\u2009cm H2O. Nonventilated animals were used for molecular biology analysis. RESULTS: At 2\u2009h, diffuse alveolar damage score and heterogeneity index were greater in the longer adaptation time group than in the control and shorter adaptation time animals. Gene expression of interleukin-6 favored the shorter (median [interquartile range], 12.4 [9.1-17.8]) adaptation time compared with longer (76.7 [20.8 to 95.4]; P = 0.02) and no adaptation (65.5 [18.1 to 129.4]) time (P = 0.02) strategies. Amphiregulin, metalloproteinase-9, club cell secretory protein-16, and syndecan showed similar behavior. CONCLUSIONS: In experimental mild acute respiratory distress syndrome, lung damage in the shorter adaptation time group compared with the no adaptation time group was attenuated in a time-dependent fashion by preemptive adaptation of the alveolar epithelial cells and extracellular matrix. Extending the adaptation period increased cumulative power and did not prevent lung damage, because it may have exposed animals to injurious strain earlier and for a longer time, thereby negating any adaptive benefit

Effects of pressure support and pressurecontrolled ventilation on lung damage in a model of mild extrapulmonary acute lung injury with intra-abdominal hypertension

Intra-abdominal hypertension (IAH) may co-occur with the acute respiratory distress syndrome (ARDS), with significant impact on morbidity and mortality. Lung-protective controlled mechanical ventilation with low tidal volume and positive end-expiratory pressure (PEEP) has been recommended in ARDS. However, mechanical ventilation with spontaneous breathing activity may be beneficial to lung function and reduce lung damage in mild ARDS. We hypothesized that preserving spontaneous breathing activity during pressure support ventilation (PSV) would improve respiratory function and minimize ventilator-induced lung injury (VILI) compared to pressure-controlled ventilation (PCV) in mild extrapulmonary acute lung injury (ALI) with IAH. Thirty Wistar rats (334\ub155g) received Escherichia coli lipopolysaccharide intraperitoneally (1000\u3bcg) to induce mild extrapulmonary ALI. After 24h, animals were anesthetized and randomized to receive PCV or PSV. They were then further randomized into subgroups without or with IAH (15 mmHg) and ventilated with PCV or PSV (PEEP = 5cmH2O, driving pressure adjusted to achieve tidal volume = 6mL/kg) for 1h. Six of the 30 rats were used for molecular biology analysis and were not mechanically ventilated. The main outcome was the effect of PCV versus PSV on mRNA expression of interleukin (IL)-6 in lung tissue. Regardless of whether IAH was present, PSV resulted in lower mean airway pressure (with no differences in peak airway or peak and mean transpulmonary pressures) and less mRNA expression of biomarkers associated with lung inflammation (IL-6) and fibrogenesis (type III procollagen) than PCV. In the presence of IAH, PSV improved oxygenation; decreased alveolar collapse, interstitial edema, and diffuse alveolar damage; and increased expression of surfactant protein B as compared to PCV. In this experimental model of mild extrapulmonary ALI associated with IAH, PSV compared to PCV improved lung function and morphology and reduced type 2 epithelial cell damage

Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension

Abstract Background Experimental research has reported beneficial effects of mesenchymal stromal cell (MSC) therapy in pulmonary arterial hypertension (PAH). However, these studies either were based on prophylactic protocols or assessed basic remodeling features without evaluating possible mechanisms. We analyzed the effects of MSC therapy on lung vascular remodeling and hemodynamics and its possible mechanisms of action in monocrotaline (MCT)-induced PAH. Methods Twenty-eight Wistar rats were randomly divided into two groups. In the PAH group, animals received MCT 60 mg/kg intraperitoneally, while a control group received saline (SAL) instead. On day 14, both groups were further randomized to receive 105 adipose-derived MSCs or SAL intravenously (n = 7/group). On day 28, right ventricular systolic pressure (RVSP) and the gene expression of mediators associated with apoptosis, inflammation, fibrosis, Smad-1 levels, cell proliferation, and endothelial–mesenchymal transition were determined. In addition, lung histology (smooth muscle cell proliferation and plexiform-like injuries), CD68+ and CD163+ macrophages, and plasma levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) were evaluated. Results In the PAH group, adipose-derived MSCs, compared to SAL, reduced mean RVSP (29 ± 1 vs 39 ± 2 mmHg, p < 0.001), lung tissue collagen fiber content, smooth muscle cell proliferation, CD68+ macrophages, interleukin-6 expression, and the antiapoptotic mediators Bcl-2 and survivin. Conversely, expression of the proapoptotic mediator procaspase-3 and plasma VEGF increased, with no changes in PDGF. In the pulmonary artery, MSCs dampened the endothelial–mesenchymal transition. Conclusion In MCT-induced PAH, MSC therapy reduced lung vascular remodeling, thus improving hemodynamics. These beneficial effects were associated with increased levels of proapoptotic markers, mesenchymal-to-endothelial transition, reduced cell proliferation markers, and inflammation due to a shift away from the M1 phenotype

Arterial blood gases at Start and End.

<p>Arterial blood gases at Start and End.</p

Real-time polymerase chain reaction analysis of biological markers associated with inflammation (interleukin [IL]-6), fibrogenesis (type III procollagen [PCIII]), pulmonary stretch (amphiregulin), type II epithelial cell damage (surfactant protein [SP]-B), and endothelial cell damage (vascular cellular adhesion molecule [VCAM-1]) in animals with normal intra-abdominal pressure (nIAP) or intra-abdominal hypertension (IAH) mechanically ventilated in pressure-controlled ventilation (PCV) or pressure support ventilation (PSV) mode.

<p>Values are given as medians, interquartile ranges, and minimum/maximum of 6 animals in each group. Relative gene expression was calculated as a ratio of average gene expression compared with the reference gene (<i>36B4</i>) and expressed as fold change relative to non-ventilated (NV) animals. *Significantly different from NV (p<0.05). #Significantly different from PCV (p<0.05).</p

Respiratory parameters at Start and End.

<p>Respiratory parameters at Start and End.</p

Timeline representation of the experimental protocol.

<p>First randomization: pressure-controlled ventilation (PCV) or pressure support ventilation (PSV). Second randomization: intra-abdominal hypertension (IAH) or normal intra-abdominal pressure (nIAP). Start: immediately after surgery (Sham) or IAH induction at PCV or PSV. V_T, tidal volume; PEEP, positive-end expiratory pressure; FiO₂, fraction of inspired oxygen. Mechanics and arterial blood gases were evaluated at Start and End (after 1 h of mechanical ventilation in PCV or PSV).</p

Cumulative DAD score (scores arithmetically averaged from two independent investigators) representing injury from alveolar collapse, interstitial edema, and septal thickening in animals with normal intra-abdominal pressure (nIAP) or intra-abdominal hypertension (IAH) mechanically ventilated in pressure-controlled ventilation (PCV) or pressure support ventilation (PSV) mode.

<p>NV: non-ventilated animals. Values are given as medians, interquartile ranges, and minimum/maximum of 6 animals in each group. Statistical significance was accepted at p < 0.05. *Significantly different from NV.</p