Lack of effect of proteinase-activated receptor-2 (PAR-2) deletion on the pathophysiological changes produced by lipopolysaccharide in the mouse: comparison with dexamethasone

Kazerani, Hamid Reza; Plevin, Robin; Kawagoe, J.; Kanke, Toru; Furman, Brian L.

doi:10.1211/0022357043923

Cited by 8 publications

(10 citation statements)

References 25 publications

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“…Pawlinski and colleagues [110] demonstrated that the deficiency of PAR 1 or PAR 2 alone did not affect mouse survival in a model of endotoxemia. The lack of any significant effect of the PAR 2 deficiency at the pathophysiological changes induced by LPS in the mouse was also confirmed in the work of Kazerani and coauthors [111]. However, an application of hirudin (a thrombin inhibitor) in PAR 2 knockout mice protected these animals better than PAR 2 wild-type mice against LPS-induced lethality [110].…”

Section: Pars and Endotoxemia Modelsmentioning

confidence: 71%

Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity

Shpacovitch

Feld

Hollenberg

et al. 2008

Journal of Leukocyte Biology

171

135

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Serine proteases are well known as enzymes involved in digestion of dietary proteins, blood coagulation, and homeostasis. Only recent groundbreaking studies revealed a novel role of serine proteases as signaling molecules acting via protease-activated receptors (PARs). Important effects of PAR activation on leukocyte motility, cytokine production, adhesion molecule expression, and a variety of other physiological or pathophysiological functions have been described in vitro and in vivo. The crucial role of PAR activation during disease progression was revealed in animal models of different gastrointestinal pathologies, neuroinflammatory and neurodegenerative processes, skin, joint and airway inflammation, or allergic responses. This review focuses on the findings related to the impact of PAR deficiency in animal models of inflammatory and allergic diseases. Additionally, we observe the role of PAR activation in the regulation of functional responses of innate and adaptive immune cells in vitro. Understanding the mechanisms by which PARs exert the effects of serine proteases on immune cells may lead to new therapeutic strategies in inflammation, immune defense, and allergy.

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Section: Pars and Endotoxemia Modelsmentioning

confidence: 71%

Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity

Shpacovitch

Feld

Hollenberg

et al. 2008

Journal of Leukocyte Biology

171

135

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“…In agreement with this, PAR-2-deficient mice, compared with wild-type animals, showed lowered leukocyte rolling and reduced content of myeloperoxidase, a neutrophil marker. This was seen after surgical trauma and LPS-induced damage, respectively (35,43).…”

Section: Discussionmentioning

confidence: 91%

PAR-2 activation and LPS synergistically enhance inflammatory signaling in airway epithelial cells by raising PAR expression level and interleukin-8 release

Ostrowska

Sokolova²,

Reiser³

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Protease-activated receptors (PARs) are involved in the contribution of airway epithelial cells to the development of inflammation by release of pro- and anti-inflammatory mediators. Here, we evaluated in epithelial cells the influence of LPS and continuous PAR activation on PAR expression level and the release of the proinflammatory chemokine IL-8. We studied primary human small airway epithelial cells and two airway epithelial cell lines, A549 and HBE cells. LPS specifically upregulated expression of PAR-2 but not of PAR-1. Exposure of epithelial cells to PAR-1 or PAR-2 agonists increased the PAR-1 expression level. The PAR-2 agonist exhibited higher potency than PAR-1 activators. However, the combined exposure of epithelial cells to LPS and PAR agonists abrogated the PAR-1 upregulation. The PAR-2 expression level was also upregulated after exposure to PAR-1 or PAR-2 agonists. This elevation was higher than the effect of PAR agonists on the PAR-1 level. In contrast to the PAR-1 level, the PAR-2 level remained elevated under concomitant stimulation with LPS and PAR-2 agonist. Furthermore, activation of PAR-2, but not of PAR-1, caused production of IL-8 from the epithelial cells. Interestingly, both in the epithelial cell line and in primary epithelial cells, there was a potentiation of the stimulation of the IL-8 synthesis and release by PAR-2 agonist together with LPS. In summary, these results underline the important role of PAR-2 in human lung epithelial cells. Moreover, our study shows an intricate interplay between LPS and PAR agonists in affecting PAR regulation and IL-8 production.

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“…Endotoxaemia also leads to hepatocellular injury and dysfunction. Consequently, an elevation of the serum ALT levels has been reported in different studies [14,23]. Furthermore, LPS increases serum creatinine and bilirubin as a result of renal damage [14,23].…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, an elevation of the serum ALT levels has been reported in different studies [14,23]. Furthermore, LPS increases serum creatinine and bilirubin as a result of renal damage [14,23]. Similarly, systemic LPS is associated with acute pancreatic damage/dysfunction [24], and different studies indicate accompanied increases in serum lipase levels [14,23,25].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, LPS increases serum creatinine and bilirubin as a result of renal damage [14,23]. Similarly, systemic LPS is associated with acute pancreatic damage/dysfunction [24], and different studies indicate accompanied increases in serum lipase levels [14,23,25]. In addition to the whole-body inflammatory response, endotoxaemia causes marked hypoglycaemia [14,15,23], presumably because of increased glucose catabolism [26,27], depletion of hepatic glycogen [28,29] and impaired gluconeogenesis [28,30].…”

Section: Discussionmentioning

confidence: 99%

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Comparison of urethane/chloralose and pentobarbitone anaesthesia for examining effects of bacterial lipopolysaccharide in mice

Kazerani

Furman

2006

Fundamemntal Clinical Pharma

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Although anaesthetics are widely used to alleviate stress in endotoxaemic animals, these drugs themselves may interfere with the effects of lipopolysaccharide (LPS). The effects of LPS on serum glucose, biochemical markers of hepatic, renal and pancreatic exocrine function, and lung myeloperoxidase (MPO) activity were compared using anaesthesia with either urethane/chloralose or pentobarbitone. Groups of 10-13 of C57B1/6 mice (22.3 +/- 0.18 g) were treated with 40 mg/kg LPS or the same volume of saline (10 mL/kg, i.p.) at time 0, Animals were anaesthetized either with urethane (1000 mg/kg) and chloralose (50 mg/kg) or with pentobarbitone (90 mg/kg, i.p.) after 2 h and blood and lung samples obtained after 6 h. In pentobarbitone-anaesthetized mice, LPS caused hypoglycaemia and increased serum levels of alanine aminotransferase (ALT), lipase and creatinine suggesting damage/dysfunction of liver, exocrine pancreas and kidney respectively. Lung tissue MPO activity, an indicator of neutrophil infiltration, was also increased. Urethane/chloralose-treated mice demonstrated hypoglycaemia and enhanced serum levels of ALT and creatinine in response to LPS, but failed to show LPS-induced increases in serum lipase and lung MPO activity. It is concluded that while pentobarbitone may be successfully used in experimental models of endotoxaemia in mice, anaesthesia with urethane and chloralose may protect mice against LPS-mediated damage/dysfunction in the exocrine pancreas and in the lung, and therefore, is not recommended in studies on endotoxaemic mice.

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Lack of effect of proteinase-activated receptor-2 (PAR-2) deletion on the pathophysiological changes produced by lipopolysaccharide in the mouse: comparison with dexamethasone

Cited by 8 publications

References 25 publications

Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity

Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity

PAR-2 activation and LPS synergistically enhance inflammatory signaling in airway epithelial cells by raising PAR expression level and interleukin-8 release

Comparison of urethane/chloralose and pentobarbitone anaesthesia for examining effects of bacterial lipopolysaccharide in mice

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