Mechanical Ventilation-induced Lung Injury Research Articles

A Pumpless Lung Assist Device Reduces Mechanical Ventilation-Induced Lung Injury in Juvenile Piglets

Respiratory failure is a major contributor to mortality and morbidity in newborn infants. The lung assist device (LAD) is a novel gas exchange device that supplements mechanical ventilation. The objective is to test the effect of the LAD on pulmonary histopathology in juvenile piglets with acute lung injury caused by saline lung lavage (SLL) followed by intermittent mandatory ventilation (IMV). Three- to 4-wk-old piglets were randomized to no intervention (control group), SLL alone (SLL group), SLL + IMV (IMV group), or SLL + IMV + LAD (LAD group) (n = 6 per group). The carotid artery and jugular vein were cannulated and an arteriovenous circuit completed, and the LAD was inserted into this circuit. Gas exchange via the LAD was initiated by passage of 100% oxygen over the blood-carrying hollow fibers of the LAD. Hemodynamic variables were recorded. Mechanical ventilation was systematically weaned. Lung histology was scored by two observers masked to treatment group. There were no differences in hemodynamic variables between the study groups. There was a significant increase in the total lung injury score in the IMV group compared with the LAD group. The novel pumpless low-resistance LAD has shown feasibility and potential to decrease ventilator-induced lung injury in a juvenile animal model.

Mechanical stretch promotes fetal type II epithelial cell differentiation via shedding of HB‐EGF and TGF‐α

The mechanisms by which mechanical forces promote fetal lung development are not fully understood. Here, we investigated differentiation of fetal type II epithelial cells via the epidermal growth factor receptor (EGFR) in response to mechanical strain. First, we showed that incubation of embryonic day (E) 19 fetal type II cells with recombinant heparin-binding EGF-like growth factor (HB-EGF) or transforming growth factor (TGF)-alpha, but not with amphiregulin (AR), betacellulin (BTC) or epiregulin (EPR), increased fetal type II cell differentiation, as measured by surfactant protein B/C mRNA and protein levels. Next, we demonstrated that 5% cyclic stretch of E19 monolayers transfected with plasmid encoding alkaline phosphatase (AP)-tagged ligands shed mature HB-EGF and TGF-alpha into the supernatant and promoted type II cell differentiation. Release of these ligands was also observed in E19 cells subjected to higher degrees of cyclic strain, but not in cells exposed to continuous stretch. Interestingly, the addition of fibroblasts to type II cell cultures did not enhance release of HB-EGF. Whereas HB-EGF shedding was also detected in E18 cells exposed to 5% cyclic stretch, release of this ligand after 2.5% sustained stretch was restricted to cells isolated on E18 of gestation. In addition, mechanical stretch released EGF, AR and BTC. We conclude that mechanical stretch promotes fetal type II cell differentiation via ectodomain shedding of HB-EGF and TGF-alpha. The magnitude of shedding varied depending on gestational age, ligand, and strain protocol. These studies provide novel mechanistic information potentially relevant to fetal lung development and to mechanical ventilation-induced lung injury.

Epidermal Growth Factor receptor (EGFR) regulates mechanical ventilation–induced lung injury in mice

Mechanical ventilation (MV) is used as therapy to support critically ill patients; however, the mechanisms by which MV induces lung injury and inflammation remain unclear. Epidermal growth factor receptor (EGFR)-mediated signaling plays a key role in various physiologic and pathologic processes, which include those modulated by mechanical and shear forces, in various cell types. We hypothesized that EGFR-activated signaling plays a key role in ventilator-induced lung injury and inflammation (VILI). To test this hypothesis, we assessed lung vascular and alveolar permeability as well as inflammation, which are cardinal features of VILI, in mice treated with the EGFR inhibitor AG1478. Inhibition of EGFR activity greatly diminished MV-induced lung alveolar permeability and neutrophil accumulation in the bronchoalveolar lavage (BAL) fluid, as compared with vehicle-treated controls. Similarly, AG1478 inhibition diminished lung vascular leak (as assessed by Evans blue extravasation), but it did not affect interstitial neutrophil accumulation. Inhibition of the EGFR pathway also blocked expression of genes induced by MV. However, intratracheal instillation of EGF alone failed to induce lung injury. Collectively, our findings suggest that EGFR-activated signaling is necessary but not sufficient to produce acute lung injury in mice.

A transgenic mouse with vascular endothelial over-expression of the non-muscle myosin light chain kinase-2 isoform is susceptible to inflammatory lung injury: role of sexual dimorphism and age

We have generated genetically engineered mice that are uniquely susceptible to lipopolysaccharide (LPS)-induced and mechanical ventilation-induced lung injury in a sex-specific and age-specific manner. These mice express a nonmuscle isoform of the myosin light chain kinase gene (nmMLCK2) targeted to the endothelium. Homozygous mice have significantly reduced fecundity and litter survival until weaning, and they are initially growth delayed but eventually exceed the size of wild-type littermates. Mice at all ages show increased protein transport across the lung barrier; however, the phenotype is most discernible in 8-12-week-old male mice. When subjected to a clinically relevant LPS-induced lung injury model, 8-12-week-old young females and 30-36-week-old males seem to be the most significantly injured group. In contrast, 30-36-week-old males remain the most significantly injured group when mechanically ventilated at high tidal volumes, which is a clinically relevant model of mechanical stress lung injury. These data reveal that nmMLCK2 overexpression in the endothelium exacerbates lung injury in vivo in a sexually dimorphic and age-dependent manner.

Effect of positive end-expiratory pressure and tidal volume on lung injury induced by alveolar instability.

IntroductionOne potential mechanism of ventilator-induced lung injury (VILI) is due to shear stresses associated with alveolar instability (recruitment/derecruitment). It has been postulated that the optimal combination of tidal volume (Vt) and positive end-expiratory pressure (PEEP) stabilizes alveoli, thus diminishing recruitment/derecruitment and reducing VILI. In this study we directly visualized the effect of Vt and PEEP on alveolar mechanics and correlated alveolar stability with lung injury.MethodsIn vivo microscopy was utilized in a surfactant deactivation porcine ARDS model to observe the effects of Vt and PEEP on alveolar mechanics. In phase I (n = 3), nine combinations of Vt and PEEP were evaluated to determine which combination resulted in the most and least alveolar instability. In phase II (n = 6), data from phase I were utilized to separate animals into two groups based on the combination of Vt and PEEP that caused the most alveolar stability (high Vt [15 cc/kg] plus low PEEP [5 cmH2O]) and least alveolar stability (low Vt [6 cc/kg] and plus PEEP [20 cmH2O]). The animals were ventilated for three hours following lung injury, with in vivo alveolar stability measured and VILI assessed by lung function, blood gases, morphometrically, and by changes in inflammatory mediators.ResultsHigh Vt/low PEEP resulted in the most alveolar instability and lung injury, as indicated by lung function and morphometric analysis of lung tissue. Low Vt/high PEEP stabilized alveoli, improved oxygenation, and reduced lung injury. There were no significant differences between groups in plasma or bronchoalveolar lavage cytokines or proteases.ConclusionA ventilatory strategy employing high Vt and low PEEP causes alveolar instability, and to our knowledge this is the first study to confirm this finding by direct visualization. These studies demonstrate that low Vt and high PEEP work synergistically to stabilize alveoli, although increased PEEP is more effective at stabilizing alveoli than reduced Vt. In this animal model of ARDS, alveolar instability results in lung injury (VILI) with minimal changes in plasma and bronchoalveolar lavage cytokines and proteases. This suggests that the mechanism of lung injury in the high Vt/low PEEP group was mechanical, not inflammatory in nature.

La eterna promesa de la ventilación de alta frecuencia

High frequency oscillatory ventilation (HFOV) is based on the application of continuous pressure in the respiratory system, which assures oxygenation, on which a small oscillation that permits ventilation is added. Although this ventilation form seems to comply with the requirements necessary to minimize the pulmonary lesion associated to mechanical ventilator-induced lung injury in acute lung injury, as several experimental studies suggest, its advantages in the clinical practice must still be demonstrated. Part of this lack of evidence is due to methodological problems of the studies published. However, the major limitation is that it has not been compared against a conventional ventilation strategy with low volumes/pressures. At present, it seems that high frequency ventilation is limited to cases refractory to conventional ventilation. A more extensive knowledge on how to optimize high frequency ventilation is needed before proposing clinical trials having greater scope.

Dynamic alveolar mechanics and ventilator-induced lung injury

To review the mechanism of dynamic alveolar mechanics (i.e., the dynamic change in alveolar size and shape during ventilation) in both the normal and acutely injured lung; to investigate the alteration in alveolar mechanics secondary to acute lung injury as a mechanism of ventilator-induced lung injury (VILI); and to examine the hypothesis that the reduced morbidity and mortality associated with protective strategies of mechanical ventilation is related to the normalization of alveolar mechanics. This review is based on original published articles and review papers dealing with the mechanism of lung volume change at the alveolar level and the role of altered alveolar mechanics as a mechanism of VILI. In addition, data from our laboratory directly visualizing dynamic alveolar mechanics is reviewed and related to the literature. The mechanism of alveolar inflation in normal lungs is unclear. Nonetheless, normal alveoli are very stable and change size very little with ventilation. Acute lung injury causes marked destabilization of individual alveoli. Alveolar instability causes pulmonary damage and is believed to be a major component in the mechanism of VILI. Ventilator strategies that reduce alveolar instability may potentially reduce the morbidity and mortality associated with VILI.

Altered alveolar mechanics in the acutely injured lung.

Alterations in alveolar mechanics (i.e., the dynamic change in alveolar size during tidal ventilation) are thought to play a critical role in acute lung injuries such as acute respiratory distress syndrome (ARDS). In this study, we describe and quantify the dynamic changes in alveolar mechanics of individual alveoli in a porcine ARDS model by direct visualization using in vivo microscopy. Prospective, observational, controlled study. University research laboratory. Ten adult pigs. Pigs were anesthetized and placed on mechanical ventilation, underwent a left thoracotomy, and were separated into the following two groups post hoc: a control group of instrumented animals with no lung injury (n = 5), and a lung injury group in which lung injury was induced by tracheal Tween instillation, causing surfactant deactivation (n = 5). Pulmonary and systemic hemodynamics, blood gases, lung pressures, subpleural blood flow (laser Doppler), and alveolar mechanics (in vivo microscopy) were measured in both groups. Alveolar size was measured at peak inspiration (I) and end expiration (E) on individual subpleural alveoli by image analysis. Histologic sections of lung tissue were taken at necropsy from the injury group. In the acutely injured lung, three distinct alveolar inflation-deflation patterns were observed and classified: type I alveoli (n = 37) changed size minimally (I - EDelta = 367 +/- 88 microm2) during tidal ventilation; type II alveoli (n = 37) changed size dramatically (I - EDelta = 9326 +/- 1010 microm2) with tidal ventilation but did not totally collapse at end expiration; and type III alveoli (n = 12) demonstrated an even greater size change than did type II alveoli (I - EDelta = 15,418 +/- 1995 microm2), and were distinguished from type II in that they totally collapsed at end expiration (atelectasis) and reinflated during inspiration. We have termed the abnormal alveolar inflation pattern of type II and III alveoli "repetitive alveolar collapse and expansion" (RACE). RACE describes all alveoli that visibly change volume with ventilation, regardless of whether these alveoli collapse totally (type III) at end expiration. Thus, the term "collapse" in RACE refers to a visibly obvious collapse of the alveolus during expiration, whether this collapse is total or partial. In the normal lung, all alveoli measured exhibited type I mechanics. Alveoli were significantly larger at peak inspiration in type II (18,266 +/- 1317 microm2, n = 37) and III (15,418 +/- 1995 microm2, n = 12) alveoli as compared with type I (8214 +/- 655 microm2, n = 37). Tween caused a heterogenous lung injury with areas of normal alveolar mechanics adjacent to areas of abnormal alveolar mechanics. Subsequent histologic sections from normal areas exhibited no pathology, whereas lung tissue from areas with RACE mechanics demonstrated alveolar collapse, atelectasis, and leukocyte infiltration. Alveolar mechanics are altered in the acutely injured lung as demonstrated by the development of alveolar instability (RACE) and the increase in alveolar size at peak inspiration. Alveolar instability varied from alveolus to alveolus in the same microscopic field and included alveoli that changed area greatly with tidal ventilation but remained patent at end expiration and those that totally collapsed and reexpanded with each breath. Thus, alterations in alveolar mechanics in the acutely injured lung are complex, and attempts to assess what may be occurring at the alveolar level from analysis of inflection points on the whole-lung pressure/volume curve are likely to be erroneous. We speculate that the mechanism of ventilator-induced lung injury may involve altered alveolar mechanics, specifically RACE and alveolar overdistension.

Pulmonary vascular interdependence in excised dog lobes.

ArticlePulmonary vascular interdependence in excised dog lobes.J J Benjamin, P S Murtagh, D F Proctor, H A Menkes, and S PermuttJ J Benjamin, P S Murtagh, D F Proctor, H A Menkes, and S PermuttPublished Online:01 Dec 1974https://doi.org/10.1152/jappl.1974.37.6.887MoreSectionsPDF (2 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByRespiratory‐Cardiovascular Interactions During Mechanical Ventilation: Physiology and Clinical Implications26 April 2022The development of various forms of lung injury with increasing tidal volume in normal ratsRespiratory Physiology & Neurobiology, Vol. 274Lung Circulation15 March 2016Non-uniform central airways ventilation model based on vascular segmentationComputers in Biology and Medicine, Vol. 65Pulmonary HemodynamicsRelease the PressureAnnals of the American Thoracic Society, Vol. 11, No. 4Mechanical interactions between adjacent airways in the lungBaoshun Ma, and Jason H. T. Bates15 March 2014 | Journal of Applied Physiology, Vol. 116, No. 6Influence of parenchymal heterogeneity on airway-parenchymal interdependenceRespiratory Physiology & Neurobiology, Vol. 188, No. 2Ventilator-induced lung injury: historical perspectives and clinical implications23 July 2011 | Annals of Intensive Care, Vol. 1, No. 1Ventilator-Induced Lung InjuryVentilator-Induced Lung InjuryFlow and pressure distributions in vascular networks consisting of distensible vesselsGary S. Krenz, and Christopher A. Dawson1 June 2003 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 284, No. 6Relative roles of vascular and airspace pressures in ventilator-induced lung injuryCritical Care Medicine, Vol. 29, No. 8Mechanical dissociation of bronchi from parenchyma in the immature piglet lungAnthony L. Mansell, Allison L. McAteer, and Eben H. Oldmixon1 July 2000 | Journal of Applied Physiology, Vol. 89, No. 1Effects of Decreased Respiratory Frequency on Ventilator-induced Lung InjuryAmerican Journal of Respiratory and Critical Care Medicine, Vol. 161, No. 2Ventilator-induced Lung InjuryAmerican Journal of Respiratory and Critical Care Medicine, Vol. 157, No. 1HEMODYNAMICS AND POSITIVE END-EXPIRATORY PRESSURE IN CRITICALLY ILL PATIENTSCritical Care Clinics, Vol. 12, No. 4Maturation of interdependence between extra-alveolar arteries and lung parenchyma in piglets.Circulation Research, Vol. 71, No. 3Regional compliance and bronchial pressure-diameter relationships in excised pig lungsRespiration Physiology, Vol. 86, No. 1Pulmonary interstitial resistanceAnnals of Biomedical Engineering, Vol. 15, No. 2Collateral Flow1 January 2011Effect of circulatory mechanics on hydrostatic forces producing pulmonary edemaJournal of Critical Care, Vol. 1, No. 4Pulmonary Circulation1 January 2011Pulmonary Interstitial Spaces and Lymphatics1 January 2011Effect of lung surface tension on pulmonary vascular mechanics in excised dog lungsRespiration Physiology, Vol. 56, No. 1Pulmonary Function and Exercise TestingBlood Flow in the LungPulmonary Circulation1 January 2011Mechanical factors determining pulmonary interstitial fluid pressureLung, Vol. 160, No. 1Effect of transpulmonary pressure on blood-flow velocity in pulmonary microvesselsRespiration Physiology, Vol. 43, No. 1Effects of spontaneous respiration on canine left ventricular function.Circulation Research, Vol. 45, No. 6Elastic properties of lung parenchyma: The effect of pressure-volume hysteresis on the behavior of large blood vesselsJournal of Biomechanics, Vol. 12, No. 10Influence of hematocrit, blood gas tensions, and pH on pressure-flow relations in the isolated canine lung.Circulation Research, Vol. 37, No. 5VILI: Physiological EvidenceCellular response to mechanical stressUnderstanding the Mechanism of Ventilator-Induced Lung Injury More from this issue > Volume 37Issue 6December 1974Pages 887-94 https://doi.org/10.1152/jappl.1974.37.6.887PubMed4436220History Published online 1 December 1974 Published in print 1 December 1974 Metrics