Proteinase activated receptor‐2‐mediated dual oxidase‐2 up‐regulation is involved in enhanced airway reactivity and inflammation in a mouse model of allergic asthma

Abstract

SummaryAirway epithelial cells (AECs) express a variety of receptors, which sense danger signals from various aeroallergens/pathogens being inhaled constantly. Proteinase-activated receptor 2 (PAR-2) is one such receptor and is activated by cockroach allergens, which have intrinsic serine proteinase activity. Recently, dual oxidases (DUOX), especially DUOX-2, have been shown to be involved in airway inflammation in response to Toll-like receptor activation. However, the association between PAR-2 and DUOX-2 has not been explored in airways of allergic mice. Therefore, this study investigated the contribution of DUOX-2/reactive oxygen species (ROS) signalling in airway reactivity and inflammation after PAR-2 activation. Mice were sensitized intraperitoneally with intact cockroach allergen extract (CE) in the presence of aluminium hydroxide followed by intranasal challenge with CE. Mice were then assessed for airway reactivity, inflammation, oxidative stress (DUOX-2, ROS, inducible nitric oxide synthase, nitrite, nitrotyrosine and protein carbonyls) and apoptosis (Bax, Bcl-2, caspase-3). Challenge with CE led to up-regulation of DUOX-2 and ROS in AECs with concomitant increases in airway reactivity/inflammation and parameters of oxidative stress, and apoptosis. All of these changes were significantly inhibited by intranasal administration of ENMD-1068, a small molecule antagonist of PAR-2 in allergic mice. Administration of diphenyliodonium to allergic mice also led to improvement of allergic airway responses via inhibition of the DUOX-2/ROS pathway; however, these effects were less pronounced than PAR-2 antagonism. The current study suggests that PAR-2 activation leads to up-regulation of the DUOX-2/ROS pathway in AECs, which is involved in regulation of airway reactivity and inflammation via oxidative stress and apoptosis.

TLR-7 agonist attenuates airway reactivity and inflammation through Nrf2-mediated antioxidant protection in a murine model of allergic asthma

“…This has been confirmed by ROS scavengers which attenuate allergen induced airway hyperresponsiveness and inflammation in various animal models of asthma (Nadeem et al, 2014b;Peh et al, 2015). Furthermore, different isoforms of NOX have been shown to regulate airway inflammation and hyperreactivity in both animal and human studies (Sutcliffe et al, 2012;Nadeem et al, 2014bNadeem et al, , 2015Voraphani et al, 2014). However, to the best of our knowledge, no study has investigated the effect of TLR-7 activation on NOX-2/NOX-4 signaling during allergic responses in a murine model of asthma.…”

“…Emerging evidence suggests that NOX-derived ROS contribute to diverse signaling processes, including TLR-induced inflammation (Amatore et al, 2015;Nadeem et al, 2015;Yang et al, 2013). For example, it has been demonstrated that NOX-2 plays an important role in TLR-2 as well as TLR-3 dependent inflammatory responses and antimicrobial activity against pathogens.…”

Recent developments in the role of reactive oxygen species in allergic asthma

“…These findings indicate that autophagy is essential for IL-13 to modulate ROS and mucus formation in epithelial cells during asthma (38). A study suggested that proteinaseactivated receptor 2 (PAR-2) is involved in airway inflammation regulation through oxidative stress, leading to increased DUOX-2/ROS pathway activation in airway epithelial cells (39). In human bronchial epithelial cells, lack of glutathione S-transferase Mu 1 (GSTM1) enhances ozone-induced IL-8 production because of ROS generation and subsequent NF-κB activation (40).…”

“…PAR-2 mediated DUOX-2 and ROS in airway epithelial cells in a cockroach allergen mice model. However, ENMD-1068, a small molecule antagonist of PAR-2, can inhibit DUOX-2 and ROS in allergic mice (39). NLRP3 inflammasome assembly is activated by mitochondrial ROS, which consequently induces IL-1β production and release (36).…”

“…Accumulating evidence suggests that TLRassociated inflammation is involved in NOX-deriving ROS generation (39). It was shown that the TLR7 activation is protective in mouse models of asthma.…”