Abstract

Background:Poly(ADP-ribose) polymerase-1 (PARP-1), a monomeric nuclear enzyme present in eukaryotes, plays a role in cell death, inflammatory mediator expression, and mononuclear cell recruitment in various experimental models of inflammation and reperfusion injury. Part of the molecular mechanism of this function involves the regulation of cytokine and chemokine production. Since chemokines are principal regulators of mononuclear and polymorphonuclear cell trafficking in asthma, we investigated the possibility whether PARP modulates chemokine production and cell recruitment in a murine model of asthma.Material/Methods: We studied ovalbumin-sensitized mice challenged with a single dose of ovalbumin.Results: PARP inhibition with the phenanthridinone-based PARP inhibitor PJ34 suppressed inflammatory cell migration. These effects were associated with downregulation of the CC chemokine MIP-1alpha, but not the CXC chemokine MIP-2. The production of TNF- alpha and IL-12, but not IL-5 or IL-13, was also suppressed by PARP inhibition.Conclusions: Our results demonstrate the pathogenetic role of PARP activation in a murine model of asthma. PARP selectively regulates the production of certain chemokines and cytokines in this experimental model, which may be responsible for some of the observed protective effects seen in the current murine asthma model.

Keywords: Asthma - drug therapy, Bronchoalveolar Lavage, Catalysis, Cell Death, Chemokines - metabolism, Cytokines - metabolism, Enzyme Inhibitors - pharmacology, Interleukin-10 - metabolism, Interleukin-12 - metabolism, Interleukin-13 - metabolism, Interleukin-5 - metabolism, Leukocytes, Mononuclear - metabolism, Lung - pathology, Mice, Inbred BALB C, Ovalbumin - metabolism, Ovalbumin - pharmacology, Peroxidase - metabolism, Poly(ADP-ribose) Polymerases - antagonists & inhibitors, Time Factors, Tumor Necrosis Factor-alpha - metabolism, Asthma - drug therapy, Bronchoalveolar Lavage, Catalysis, Cell Death, Chemokine CXCL2, Chemokines - metabolism, Cytokines - metabolism, Enzyme Inhibitors - pharmacology, Interleukin-10 - metabolism, Interleukin-12 - metabolism, Interleukin-13 - metabolism, Interleukin-5 - metabolism, Leukocytes, Mononuclear - metabolism, Lung - pathology, Mice, Inbred BALB C, Ovalbumin - pharmacology, Peroxidase - metabolism, Poly(ADP-ribose) Polymerases - antagonists & inhibitors, Time Factors, Tumor Necrosis Factor-alpha - metabolism