Ischaemia/reperfusion, inflammatory responses and acute lung injury.

Rocker, Graeme

doi:10.1136/thx.52.10.841

Cited by 15 publications

(7 citation statements)

References 21 publications

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“…Aortic clamping and release appears to release proinflammatory cytokines, such as interleukin-8, tumor necrosis factor a, and interleukin-1b [1,2]. These mediators are powerful inducers of neutrophil activation, adhesion molecule expression, and the transepithelial migration of leukocytes into tissues [3]. Increased pulmonary microvascular responses have been demonstrated 3 h after aortic unclamping, with recovery after 24 h [4,5].…”

Section: Introductionmentioning

confidence: 93%

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Protective Role of Cyclooxygenase (COX)-2 in Experimental Lung Injury: Evidence of a Lipoxin A4-Mediated Effect

Scully

Chen

Condron

et al. 2012

Journal of Surgical Research

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Section: Introductionmentioning

confidence: 93%

“…This process is controlled by mediators, such as pro-inflammatory cytokines, leukotrienes, and prostanoids [2,3]. These mediators are capable of inducing injury in tissues remote from the site of I/R due to their systemic release.…”

Section: Introductionmentioning

confidence: 99%

Protective Role of Cyclooxygenase (COX)-2 in Experimental Lung Injury: Evidence of a Lipoxin A4-Mediated Effect

Scully

Chen

Condron

et al. 2012

Journal of Surgical Research

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“…Under normal conditions, neutrophils roll along microvascular walls. After activation by proinflammatory cytokines and chemotactic factors, neutrophils are then able to penetrate the vasculature and transmigrate through the interstitium into the alveolar space [ 18 , 19 ]. In addition, alveolar macrophages are also essential players in the initiation of ALI [ 11 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Cyclic arginine-glycine-aspartate attenuates acute lung injury in mice after intestinal ischemia/reperfusion

et al. 2013

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IntroductionIntestinal ischemia is a critical problem resulting in multiple organ failure and high mortality of 60 to 80%. Acute lung injury (ALI) is a common complication after intestinal ischemia/reperfusion (I/R) injuries and contributes to the high mortality rate. Moreover, activated neutrophil infiltration into the lungs is known to play a significant role in the progression of ALI. Integrin-mediated interaction is involved in neutrophil transmigration. Synthetic peptides containing an arginine-glycine-aspartate sequence compete with adhesive proteins and inhibit integrin-mediated interaction and signaling. Thus, we hypothesized that the administration of a cyclic arginine-glycine-aspartate peptide (cRGD) inhibited neutrophil infiltration and provided protection against ALI induced by intestinal I/R.MethodsIschemia in adult male C57BL/6 mice was induced by fastening the superior mesenteric artery with 4-0 suture. Forty-five minutes later, the vascular suture was released to allow reperfusion. cRGD (5 mg/kg body weight) or normal saline (vehicle) was administered by intraperitoneal injection 1 hour prior to ischemia. Blood, gut, and lung tissues were collected 4 hours after reperfusion for various measurements.ResultsIntestinal I/R caused severe widespread injury to the gut and lungs. Treatment with cRGD improved the integrity of microscopic structures in the gut and lungs, as judged by histological examination. Intestinal I/R induced the expression of β1, β2 and β3 integrins, intercellular adhesion molecule-1, and fibronectin. cRGD significantly inhibited myeloperoxidase activity in the gut and lungs, as well as neutrophils and macrophages infiltrating the lungs. cRGD reduced the levels of TNF-α and IL-6 in serum, in addition to IL-6 and macrophage inflammatory protein-2 in the gut and lungs. Furthermore, the number of TUNEL-staining cells and levels of cleaved caspase-3 in the lungs were significantly lowered in the cRGD-treated mice in comparison with the vehicle mice.ConclusionsTreatment with cRGD effectively protected ALI and gut injury, lowered neutrophil infiltration, suppressed inflammation, and inhibited lung apoptosis after intestinal I/R. Thus, there is potential for developing cRGD as a treatment for patients suffering from ALI caused by intestinal I/R.

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“…Once activated by proinflammatory mediators, neutrophils are able to penetrate the endothelial layer and migrate into the alveolar space [35,36]. Recruitment of neutrophils to the lung is believed to play a critical role in the progression of acute lung injury [37].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ERK1/2 Worsens Intestinal Ischemia/Reperfusion Injury

2013

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BackgroundThe role of extracellular signal-regulated protein kinase (ERK) in intestinal ischemia/reperfusion (I/R) injury has not been well investigated. The aim of the current study was to examine the effect of inhibition of the ERK pathway in an in vitro and in vivo model of intestinal I/R injury.MethodsERK1/2 activity was inhibited using the specific inhibitor, U0126, in intestinal epithelial cells under hypoxia/reoxygenation conditions and in mice subjected to 1 hour of intestinal ischemia followed by 6 hours reperfusion. In vitro, cell proliferation was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, apoptosis by DNA fragmentation, and migration using an in vitro model of intestinal wound healing. Cells were also transfected with a p70S6K plasmid and the effects of overexpression similarly analyzed. In vivo, the effects of U0126 on intestinal cell proliferation and apoptosis, intestinal permeability, lung and intestinal neutrophil infiltration and injury, and plasma cytokine levels were measured. Survival was also assessed after U0126. Activity of p70S6 kinase (p70S6K) was measured by Western blot.ResultsIn vitro, inhibition of ERK1/2 by U0126 significantly decreased cell proliferation and migration but enhanced cell apoptosis. Overexpression of p70S6K promoted cell proliferation and decreased cell apoptosis. In vivo, U0126 significantly increased cell apoptosis and decreased cell proliferation in the intestine, increased intestinal permeability, intestinal and lung neutrophil infiltration, and injury, as well as systemic pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β. Mortality was also significantly increased by U0126. Inhibition of ERK1/2 by U0126 also abolished activity of p70S6K both in vitro and in vivo models.ConclusionPharmacologic inhibition of ERK1/2 by U0126 worsens intestinal IR injury. The detrimental effects are mediated, at least in part, by inhibition of p70S6K, the major effector of mammalian target of rapamycin pathway.

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Ischaemia/reperfusion, inflammatory responses and acute lung injury.

Cited by 15 publications

References 21 publications

Protective Role of Cyclooxygenase (COX)-2 in Experimental Lung Injury: Evidence of a Lipoxin A4-Mediated Effect

Protective Role of Cyclooxygenase (COX)-2 in Experimental Lung Injury: Evidence of a Lipoxin A4-Mediated Effect

Cyclic arginine-glycine-aspartate attenuates acute lung injury in mice after intestinal ischemia/reperfusion

Inhibition of ERK1/2 Worsens Intestinal Ischemia/Reperfusion Injury

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