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Signaling mechanisms in Streptococcal M1 proteininduced inflammation and injury in the lung

Författare:
Publiceringsår: 2012
Språk: Engelska
Sidor: 72
Publikation/Tidskrift/Serie: Lund University, Faculty of Medicine Doctoral Dissertation Series
Volym: 2012:104
Dokumenttyp: Doktorsavhandling
Förlag: Surgery Research Unit, Clinical Science, Malmö

Sammanfattning

Streptococcus pyogenes of the M1 serotype is frequently associated with severe streptococcal infections.
Acute lung injury is recognized as a key component in the pathophysiology of streptococcal M1 proteininduced
inflammation. Numerous reports have demonstrated that excessive infiltration of neutrophils is a
rate-limiting step in septic lung damage. We observed that targeting neutrophil functions appeared more
relevant than inhibiting platelet activation in severe infections triggered by streptococcal M1 protein. In study
II, it was shown that simvastatin was a powerful inhibitor of neutrophil infiltration in acute lung damage
triggered by streptococcal M1 protein. The inhibitory effect of simvastatin on M1 protein-induced neutrophil
recruitment appeared related to reduced pulmonary generation of CXC chemokines. Following the mevalonate
signaling pathway, checking downstream effectors, both Rho/Rho Kinase and p38 MAPK signaling pathway
played critical roles in M1 protein-induced lung recruitment of neutrophils via formation of CXC chemokines
and Mac-1 expression. In addition, our findings also suggested that farnesyltransferase was a potent regulator
of CXC chemokine formation in alveolar macrophages and that inhibition of farnesyltransferase not only
reduces neutrophil recruitment but also attenuates acute lung injury provoked by streptococcal M1 protein.
Thus, these new data may provide a basis for the development of more specific and effective treatment of
patients with STSS.

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2012-11-30
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