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Identifier

000401037

Title

Βλάβη ισχαιμίας-επαναιμάτωσης στο γαστρεντερικό σύστημα και ο ρόλος του συμπληρώματος

Alternative Title

Complement depletion protects lupus -prone mice from ischemia-reperfusion -initiated organ injury

Author

Ιωάννου, Αντώνης

Thesis advisor

Παπαδάκης, Κωνσταντίνος
Τσώκος, Γεώργιος
Καρδάσης, Δημήτριος
Σιδηρόπουλοε, Πρόδρομος

Reviewer

Γουλιέλμος, Γιώργος
Μπερτσιάς, Γεώργιος

Abstract

1st MODULE: COMPLEMENT DEPLETION PROTECTS LUPUS-PRONE MICE FROM ISCHEMIA-REPERFUSION-INITIATED ORGAN INJURY. Ischemia-reperfusion (IR) injury causes a vigorous immune response that is amplified by complement activation, leading to local and remote tissue damage. Using MRL/lpr mice, which are known to experience accelerated tissue damage after mesenteric IR injury, we sought to evaluate whether complement inhibition mitigates organ damage. We found that complement depletion with cobra venom factor protected mice from local and remote lung tissue damage. Protection from injury was associated with less complement (C3) and membrane attack complex deposition, less neutrophil infiltration, and lower levels of local proinflammatory cytokine production. In addition, complement depletion was able to decrease the level of oxidative stress as measured by glutathione peroxidase 1 mRNA levels and superoxide dismutase activity. Furthermore, blockage of C5a receptor protected MRL/lpr mice from local tissue damage, but not from remote lung tissue damage. In conclusion, although treatments with cobra venom factor and C5a receptor antagonist were able to protect mice from local tissue damage, treatment with C5a receptor antagonist was not able to protect mice from remote lung tissue damage, implying that more factors contribute to the development of remote tissue damage after IR injury. These data also suggest that complement inhibition at earlier, rather than late, stages can have clinical benefit in conditions that are complicated with IR injury. 2nd MODULE: THE ROLE OF PLATELET FACTOR 4 IN LOCAL AND REMOTE TISSUE DAMAGE IN A MOUSE MODEL OF MESENTERIC ISCHEMIAREPERFUSION INJURY. The robust inflammatory response that occurs during ischemia reperfusion (IR) injury recruits factors from both the innate and adaptive immune systems. However the contribution of platelets and their products such as Platelet Factor 4 (PF4; CXCL4), during the pathogenesis of IR injury has not been thoroughly investigated. We show that a deficiency in PF4 protects mice from local and remote tissue damage after 30 minutes of mesenteric ischemia and 3 hours of reperfusion in PF4- /- mice compared to control B6 mice. This protection was independent from Ig or complement deposition in the tissues. However, neutrophil and monocyte infiltration were decreased in the lungs of PF4-/- mice compared with B6 control mice. Plateletdepleted B6 mice transfused with platelets from PF4-/- mice displayed reduced tissue damage compared with controls. In contrast, transfusion of B6 platelets into platelet depleted PF4-/- mice reconstituted damage in both intestine and lung tissues. We also show that PF4 may modulate the release of IgA. Interestingly, we show that PF4 expression on intestinal epithelial cells is increased after IR at both the mRNA and protein levels. In conclusion, these findings demonstrate that may PF4 represent an important mediator of local and remote tissue damage.

Language

Greek

Subject

Autoimmunity

Αιμοπετάλια

Αυτοάνοσα νοσήματα

Λεπτό έντερο

Συστηματικός ερυθηματώδης λύκος

Issue date

2015-03-27

Collection

School/Department--School of Medicine--Department of Medicine--Doctoral theses