Tezosentan-induced attenuation of lung injury in endotoxemic sheep is associated with reduced activation of protein kinase C

Kuklin, V. N.; Киров, М. Ю.; Sovershaev, Mikhail A.; Andreasen, Thomas V.; Ingebretsen, Ole C.; Ytrehus, Kirsti; Bjertnæs, Lars J.

doi:10.1186/cc3497

Cited by 37 publications

(14 citation statements)

References 36 publications

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“…Since TNF-α seems to be important for platelet P-selectin-mediated platelet/endothelial interaction and TNF-α blood concentration rises during endotoxemia [35] our results are in accordance with the literature. Our concept that platelet P-selectin may contribute to platelet/endothelial interaction might be further supported by Tailor and Granger [36].…”

Section: Discussionsupporting

confidence: 82%

Role of P-Selectin in Platelet Sequestration in Pulmonary Capillaries during Endotoxemia

Kiefmann

Heckel²,

Schenkat³

et al. 2006

J Vasc Res

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Background: There is growing evidence that platelets accumulate in the lung and contribute to the pathogenesis of acute lung injury during endotoxemia. The aims of the present study were to localize platelet sequestration in the pulmonary microcirculation and to investigate the role of P-selectin as a molecular mechanism of platelet endothelial cell interaction. Methods: We used in vivo fluorescence microscopy to quantify the kinetics of fluorescently labeled erythrocytes and platelets in alveolar capillary networks in rabbit lungs. Results: Six hours after onset of endotoxin infusion we observed a massive rolling along and firm adherence of platelets to lung capillary endothelial cells whereas under control conditions no platelet sequestration was detected. P-selectin was expressed on the surface of separated platelets which were incubated with endotoxin and in lung tissue. Pretreatment of platelets with fucoidin, a P-selectin antagonist, significantly attenuated the endotoxin-induced platelet rolling and adherence. In contrast, intravenous infusion of fucoidin in endotoxin-treated rabbits did not inhibit platelet sequestration in pulmonary capillaries. Conclusion: We conclude that platelets accumulate in alveolar capillaries following endotoxemia. P-selectin expressed on the surface of platelets seems to play an important role in mediating this platelet-endothelial cell interaction.

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Section: Discussionsupporting

confidence: 82%

Role of P-Selectin in Platelet Sequestration in Pulmonary Capillaries during Endotoxemia

Kiefmann

Heckel²,

Schenkat³

et al. 2006

J Vasc Res

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“…decreased cardiac output, vasoconstriction in the pulmonary artery, impairment of renal and splanchnic circulation (Bomberg et al 2013 ; Ross 2012 ; Schuuring et al 2013 ). It has been demonstrated in animal experiments that dual ETA/ETB endothelin blockade during endotoxaemia improves cardiopulmonary function, reduces pulmonary hypertension and lung injury and attenuates intestinal and liver microcirculatory dysfunction (Kuklin et al 2005 ; Sánchez-Etayo et al 2012 ). Also ETA receptor blockade alone improves the function of the lungs (Mercier et al 2010 ), kidney (Rullman et al 2010 ), heart (Vanêcková et al 2005 ) and aorta (Tirapelli et al 2008 ).…”

Section: Et-1 and Endothelin Receptor Antagonists In Sepsismentioning

confidence: 99%

The Role of Endothelin-1 and Endothelin Receptor Antagonists in Inflammatory Response and Sepsis

Kowalczyk

Kleniewska

Kołodziejczyk

et al. 2014

Arch. Immunol. Ther. Exp.

234

150

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Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, mainly secreted by endothelial cells. It acts through two types of receptors: ETA and ETB. Apart from a vasoconstrictive action, ET-1 causes fibrosis of the vascular cells and stimulates production of reactive oxygen species. It is claimed that ET-1 induces proinflammatory mechanisms, increasing superoxide anion production and cytokine secretion. A recent study has shown that ET-1 is involved in the activation of transcription factors such as NF-jB and expression of proinflammatory cytokines including TNF-a, IL-1, and IL-6. It has been also indicated that during endotoxaemia, the plasma level of ET-1 is increased in various animal species. Some authors indicate a clear correlation between endothelin plasma level and morbidity/mortality rate in septic patients. These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade. ET-1 receptor antagonists may be useful for prevention of various vascular diseases. This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation.

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“…Therefore, monoclonal antibodies, DNA or RNA aptamers, or small molecules that are able to interact the very C terminus of PKC␣ and suppress its catalytic activity may become invaluable tools in the study of the biology of this kinase. Moreover, such agents could represent a new generation of drugs for treating diseases in which the activation of PKC␣ is implicated, such as in heart failure and sepsis/endotoxemia (70,71).…”

Section: Discussionmentioning

confidence: 99%

The Last 10 Amino Acid Residues beyond the Hydrophobic Motif Are Critical for the Catalytic Competence and Function of Protein Kinase Cα

Yeong

Zhu

Smith

et al. 2006

Journal of Biological Chemistry

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The segment C-terminal to the hydrophobic motif at the V5 domain of protein kinase C (PKC) is the least conserved both in length and in amino acid identity among all PKC isozymes. By generating serial truncation mutants followed by biochemical and functional analyses, we show here that the very C terminus of PKC␣ is critical in conferring the full catalytic competence to the kinase and for transducing signals in cells. Deletion of one C-terminal amino acid residue caused the loss of ϳ60% of the catalytic activity of the mutant PKC␣, whereas deletion of 10 C-terminal amino acid residues abrogated the catalytic activity of PKC␣ in immune complex kinase assays. The PKC␣ C-terminal truncation mutants were found to lose their ability to activate mitogen-activated protein kinase, to rescue apoptosis induced by the inhibition of endogenous PKC in COS cells, and to augment melatonin-stimulated neurite outgrowth. Furthermore, molecular dynamics simulations revealed that the deletion of 1 or 10 C-terminal residues results in the deformation of the V5 domain and the ATP-binding pocket, respectively. Finally, PKC␣ immunoprecipitated using an antibody against its C terminus had only marginal catalytic activity compared with that of the PKC␣ immunoprecipitated by an antibody against its N terminus. Therefore, the very C-terminal tail of PKC␣ is a novel determinant of the catalytic activity of PKC and a promising target for selective modulation of PKC␣ function. Molecules that bind preferentially to the very C terminus of distinct PKC isozymes and suppress their catalytic activity may constitute a new class of selective inhibitors of PKC.

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Tezosentan-induced attenuation of lung injury in endotoxemic sheep is associated with reduced activation of protein kinase C

Cited by 37 publications

References 36 publications

Role of P-Selectin in Platelet Sequestration in Pulmonary Capillaries during Endotoxemia

Role of P-Selectin in Platelet Sequestration in Pulmonary Capillaries during Endotoxemia

The Role of Endothelin-1 and Endothelin Receptor Antagonists in Inflammatory Response and Sepsis

The Last 10 Amino Acid Residues beyond the Hydrophobic Motif Are Critical for the Catalytic Competence and Function of Protein Kinase Cα

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