Mechanical ventilation induces inflammation, lung injury, and extra-pulmonary organ dysfunction in experimental pneumonia

Dhanireddy, Shireesha; Altemeier, William A.; Matute-Bello, Gustavo; O’Mahony, D. Shane; Glenny, Robb W.; Martin, Thomas R.; Liles, W. Conrad

doi:10.1038/labinvest.3700440

Cited by 122 publications

(89 citation statements)

References 48 publications

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“…Enhanced lung injury is also seen with mechanical ventilation and Staphylococcus aureus pneumonia. The combination of ventilation and bacterial infection also augmented the injury of nonpulmonary organs, suggesting that mechanical ventilation exacerbates systemic inflammatory responses to bacteria and contributes to the pathogenesis of the multiple organ dysfunction syndrome [45].…”

Section: Epithelial Cell Responses To Mechanical Stretchmentioning

confidence: 99%

“…Numerous experimental models of VILI have demonstrated additive or synergistic effects of bacterial products with mechanical ventilation on the development or exacerbation of lung injury [44][45][46][47][48]. Mechanical ventilation using moderate tidal volumes in mice enhanced lipopolysaccharide (LPS)-induced expression of TNF-α, IL-8, growth-related protein-α and monocyte chemoattractant protein (MCP)-1 [44].…”

Section: Epithelial Cell Responses To Mechanical Stretchmentioning

confidence: 99%

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Role of the pulmonary epithelium and inflammatory signals in acute lung injury

Manicone¹

2009

Expert Review of Clinical Immunology

118

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Acute lung injury (ALI) is a clinical disease marked by respiratory failure due to disruption of the epithelial and endothelial barrier, flooding of the alveolar compartment with protein-rich fluid and recruitment of neutrophils into the alveolar space. ALI affects approximately 200,000 patients annually in the USA and results in approximately 75,000 deaths. It is associated with prolonged mechanical ventilation, intensive medical care, high morbidity and mortality, and rising healthcare costs. Owing to its impact on public health, great strides have been made towards understanding the pathobiology of ALI to affect outcome. This review will focus on the role of the epithelial cell in the pathogenesis and resolution of ALI and the role of various inflammatory mediators in ALI. Keywordsβ2-agonist; acute lung injury; acute respiratory distress syndrome; chemokine; cytokine; epithelial cell; inflammation; methylprednisolone; neutrophil; salbutamol; steroid; ventilator-induced lung injuryAcute lung injury/acute respiratory distress syndrome (ALI/ARDS) was first described in 1967 by Ashbaugh and colleagues in a group of 12 patients who shared a constellation of clinical symptoms including acute respiratory distress, hypoxemia refractory to supplemental oxygen, decreased lung compliance and diffuse pulmonary infiltrates [1]. Since this first description, the clinical criteria have evolved to include acute onset of respiratory distress, bilateral pulmonary infiltrates seen on chest radiographs, absence of left-sided heart failure and hypoxemia, with the severity of hypoxemia distinguishing ALI and ARDS (Box 1) [2]. Extrapolating from recent epidemiologic studies using these criteria, ALI affects about 200,000 patients annually in the USA and results in approximately 75,000 deaths [3]. This disease, which can be caused by common events such as pneumonia, sepsis and trauma, results in high morbidity, mortality and healthcare expenditures associated with prolonged mechanical ventilation and intensive care. Because of its impact on public health and patient outcomes, great strides have been made towards understanding the pathobiology of ALI.When defined broadly to include all processes related to defense against microbes, other environmental insults and injury, a wide variety of cell types and proteins participate in inflammation and immunity. Leukocytes are the paradigmatic inflammatory cell type, but they are not the only cells that function in defense and immunity. The epithelial lining of all tissues forms a continuous barrier to the environment and is the first line of defense against infectious agents and toxins. Though specialized to serve distinct functions among tissues, epithelial cells respond similarly to injury and infection, and regulate leukocyte influx through the production of proinflammatory cytokines, chemokines and other factors that modulate chemokine gradients and effect leukocyte migration. This review will focus on the role of the pulmonary epithelium and inflammatory mediators in ALI. More s...

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Section: Epithelial Cell Responses To Mechanical Stretchmentioning

confidence: 99%

Section: Epithelial Cell Responses To Mechanical Stretchmentioning

confidence: 99%

Role of the pulmonary epithelium and inflammatory signals in acute lung injury

Manicone¹

2009

Expert Review of Clinical Immunology

118

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“…It is generally accepted that VALI is an excessive, uncontrolled, inflammatory, response within the lung (3). Previous studies have suggested that the release of pro-inflammatory cytokines have a central role in VALI (4,5). Nuclear factor (NF)-κB is required for maximal transcription of various cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-8, and IL-1β (6,7).…”

Section: Introductionmentioning

confidence: 99%

Preconditioning of physiological cyclic stretch inhibits the inflammatory response induced by pathologically mechanical stretch in alveolar epithelial cells

Fang

et al. 2017

Exp Ther Med

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Abstract. The aim of the present study was to investigate the effects of preconditioning of physiological cyclic stretch (CS) on the overexpression of early pro-inflammatory cytokines [including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-8] during the inflammatory response induced by pathologically mechanical stretch in lung epithelial cells, and to determine its molecular mechanism of action. Cells were subjected to 5% CS for various durations (0,15, 30, 60 and 120 min) prior to 6 h treatment with pathological 20% CS. In a separate experiment, cells were preconditioned with physiological 5% CS or incubated with a nuclear factor (NF)-κB inhibitor, pyrroldine dithiocarbamate (PDTC). The expression levels of inflammatory mediators were measured using reverse transcription-quantitative polymerase chain reaction. NF-κB was quantified using western blot analysis. Preconditioning with physiological 5% CS for 30, 60 and 120 min was demonstrated to significantly attenuate the release of pathologically mechanical stretch-induced early pro-inflammatory cytokines (TNF-α, IL-1β and IL-8) in alveolar epithelial cells (P<0.05) and significantly reduce the expression of NF-κB (P<0.05). Peak suppression was observed in cells preconditioned for 60 min. In the second set of experiments, it was demonstrated that mechanical stretch-induced release of TNF-α, IL-1β and IL-8 was significantly inhibited by both PDTC pretreatment and 5% CS pretreatment alone (all P<0.05). Furthermore, significant inhibition was also observed when both 5% CS pretreatment and PDTC pretreatment was used on mechanical stretch-induced cells (P<0.05), which was markedly greater than the inhibition induced by either pretreatment alone. The present findings suggest that preconditioning with physiological 5% CS is able to inhibit the inflammatory response induced by pathologically mechanical stretch in alveolar epithelial cells. These anti-inflammatory effects are induced, at least in part, by suppressing the NF-κB signaling pathway.

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“…Such mechanical ventilation is often combined together with an infectious injury to mimic clinical sepsis-induced ALI, [ 12 ], [ 40 ], [ 42 ], [ 63 ] and [ 64 ] although the direct effect of each challenge is difficult to dissociate. We assumed that high-volume ventilation will cause mechanical stress-related injury and hypothesized that the resulting barrier dysfunction [ 65 ] and [ 66 ] will be exacerbated by increases in EC paracellular gap formation in nmMLCK2 transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

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

Moitra

Evenoski

Sammani

et al. 2008

Translational Research

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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 wildtype 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.Actin microfilaments generate force by virtue of their ability to contract away from their site of attachment to the plasma membrane, and they do so via traction of the myosin light chain head groups attached to actin filaments by cross-bridges. The cross-bridge pulling action of myosin involves a conformational change in the molecule initiated by energetic phosphorylation of Ser19 on the myosin light chains. 1 The key enzyme involved in this phosphorylation event is myosin light chain kinase (MLCK), which exists in different tissues, and it may be characterized broadly as skeletal/cardiac, smooth muscle, and nonmuscle myosin light chain kinase (nmMLCK) isoforms. Although biochemical evidence for the existence of a Ca 2+ /calmodulin-dependent nonmuscle isoform in cultured endothelial cell (EC) was suggested earlier, [ 2 ] and [ 3 ] the controversy as to whether this enzymatic activity is identical to the 110-kDa protein found abundantly in smooth muscle preparations was resolved when we provided conclusive proof of a larger MLCK protein isoform (210 kDa) by cloning the gene (MYLK) from a human EC-derived cDNA library. 4 The gene was subsequently mapped to chromosome 3q21. 5

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Mechanical ventilation induces inflammation, lung injury, and extra-pulmonary organ dysfunction in experimental pneumonia

Cited by 122 publications

References 48 publications

Role of the pulmonary epithelium and inflammatory signals in acute lung injury

Role of the pulmonary epithelium and inflammatory signals in acute lung injury

Preconditioning of physiological cyclic stretch inhibits the inflammatory response induced by pathologically mechanical stretch in alveolar epithelial cells

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

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