Increased poly(ADP-ribose) polymerase (PARP)-1 expression and activity are associated with inflammation but not goblet cell metaplasia in murine models of allergen-induced airway inflammation

Abstract

Inflammation plays a key role in lung injury and in the pathogenesis of asthma. Two murine models of allergic airway inflammation-sensitization and challenge to ovalbumin (OVA) and intratracheal exposure to interleukin-13 (IL13)-were used to evaluate the expression of poly(ADP-ribose) polymerase-1 (PARP-1) in allergic airway inflammation. Inflammation is prominent in OVA-induced allergic asthma, but this inflammation is greatly reduced by a PARP-1 inhibitor and almost eliminated when PARP-1 knockout mice are subjected to the OVA model. The present study temporally evaluated PARP-1 protein expression, localization, and activity, as well as inflammation and goblet cell metaplasia (GCM), in murine lungs following a single OVA challenge or IL13 exposure. Following OVA challenge PARP-1 protein expression and activity were greatly increased, being maximal at 3 to 5 days following OVA exposure and beginning to decrease by day 8. These changes correlated with the timing and degree of inflammation and GCM. In contrast, PARP-1 protein or activity did not change following single IL13 exposure, though GCM was manifested without inflammation. This study demonstrates that both PARP-1 protein and activity are increased by allergen-activated inflammatory mediators, excluding IL13, and that PARP-1 increase does not appear necessary for GCM, one of the characteristic markers of allergic airway inflammation in murine models.

Lipopolysaccharide activates ERK–PARP-1–RelA pathway and promotes nuclear factor–κB transcription in murine macrophages

“…The production of IL-5, IL-10, IL-13, and GM-CSF cytokines was completely inhibited in ex vivo OVA-challenged lung cells derived from these animals. These results implied the role of PARP-1 in allergy inflammation [12,13]. Moreover, the involvement of PARP-1 in the progression of atherosclerosis [14,15], diabetes complications [16,17], autoimmune nephritis [18], and spinal cord injury [19] has also been suggested.…”

Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond

“…Asthma bronchiale is another indication where multiple lines of preclinical data show that PARP inhibition/PARP deficiency attenuates inflammatory responses and improves bronchial reactivity both in pre-treatment and in delayed therapeutic regimens (Virag et al, 2004; Suzuki et al, 2004; Naura et al, 2009; Havranek et al, 2010; Datta et al, 2011). However, the experimental therapy of chronic heart failure, asthma, or some of the other indications discussed in earlier sections (e.g.…”

Beyond DNA repair, the immunological role of PARP‐1 and its siblings

“…The role of PARylation was also investigated in allergic airway inflammation. Following allergen challenge PARP‐1 protein expression and activity are greatly increased in murine lungs . Even if with some specific differences, both PARP‐1 knockout and PARP‐14 knockout mice show reduced IL‐5 and IL‐13 production (also IL‐4 in PARP‐14 knockout), eosinophilic recruitment, allergic airway inflammation, and IgE levels compared with wild‐type animals .…”