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02 May 2003 : Original article  

Therapeutic potential of PARP inhibitors in inflammatory dermatosis

L. Virag, E. Bakondi, P. Bai, K. Erdelyi, E. Szabo, P. Gergely, C. Szabo

Med Sci Monit 2003; 9(1): 75- :: ID: 15218

Abstract

Several inflammatory skin diseases are characterized by oxidative stress, i.e. production of reactive oxygen and nitrogen intermediates (ROI/RNI). These reactive species are capable of causing DNA damage and consequently PARP activation. Accumulating evidence point toward an important role of oxidative stress-induced PARP activation in various dermatological conditions. Most evidence supports the role of PARP activation in contact hypersensitivity (CHS). CHS is a form of delayed type of hypersensitivity reaction mediated mainly by T lymphocytes. The first phase of CHS is sensitization during which administration of antigens triggers the proliferation of antigen-specific T lymphocytes. In senzitized individuals, application of the same, lipofilic antigen on the skin surface results in immune-mediated inflammation (effector phase). Whereas the cellular events of the senzitization phase is well characterized, little is known about the mechanisms of the effector phase. Our previous work has demonstrated that peroxynitrite, the nitric oxide-derived reactive oxidant is produced in the oxazolone-induced murine model of contact hypersensitivity. Furthermore, we have also shown that DNA breakage and PARP activation occurs in this model. Moreover, our new data demonstrate the effectiveness of the PARP inhibitor PJ-34 in CHS. The underlining mechanisms include inhibition of migration of granulocytes, inhibition of chemokine production and prevention of keratinocyte dysfunction. Sporadic data in the literature also indicate a possible role of PARP activation in other skin diseases such as sunburn erythema, toxic epidermal necrolysis or Stevens-Johnson syndrom. Proposed mechanisms for the role of poly-ADP-ribosylation in these dermatological diseases and opportunities for therapeutic interventions will be discussed.

Keywords: peroxynitrite, poly(ADP-ribose) polymerase, Dermatitis, contact hypersensitivity, Sunburn

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750