Abstract
Exposure to fine particulate matter (PM2.5) has been associated with lung inflammation and airway hyperresponsiveness (AHR). Transient receptor potential (TRP) vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) both may play important roles in lung inflammation and AHR. We investigated whether PM2.5-induced lung inflammation and AHR could be prevented by blocking TRPV1 and TRPA1 channels. Mice were injected intraperitoneally with AMG9810 (30 mg/kg, a TRPV1 antagonist) or A967079 (30 mg/kg, a TRPA1 antagonist) or their combination or vehicle (PBS) one hour before intranasal instillation of PM2.5 (7.8 mg/kg) or vehicle (PBS) for two consecutive days, and then the mice were studied 24 h later. All pretreatments inhibited PM2.5-induced AHR and inflammatory infiltration in the lung tissue and decreased inflammatory cytokine levels in the bronchoalveolar lavage fluid, together with oxidant levels in the lung. AMG9810 inhibited MFF expression and increased MFN2 expression while A967079 inhibited DRP1 expression and increased OPA1 expression; combined pretreatment reduced MFF and DPR1 expression and increased MFN2 and OPA1 expression. All pretreatments inhibited the activation of the TLR4/NF-κB pathway, while A967079 alone, and combined with AMG9810 also reduced the activation of the NLRP3/caspase-1 pathway. Both TRPV1 and TRPA1 channels play an important role in PM2.5-induced lung inflammation and AHR. However, inhibition of the TRPA1 channel or combined inhibition of TRPA1 and TRPV1 channels resulted in greater inhibitory effect on PM2.5-induced lung injury through regulating the mitochondrial fission/fusion proteins and inhibiting the TLR4/NF-κB and NLRP3/caspase-1 pathways.
Highlights
Due to increasing urbanization and modernization, particulate matter (PM) pollution has become a serious health risk in China
The underlying mechanisms of PM2.5 toxicity may be partly explained by its ability to cause oxidative stress and mitochondrial damage [4], a process that involves the activation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and nucleotide binding domain leucinerich repeat-containing receptors (NLRs) [5]
We demonstrated that PM2.5 intranasal instillation induced lung inflammation, airway hyperresponsiveness (AHR), and oxidative stress in mice and separate or combined pretreatment with AMG9810 or/and A967079 attenuated PM2.5-induced lung inflammation, AHR, and oxidative stress
Summary
Due to increasing urbanization and modernization, particulate matter (PM) pollution has become a serious health risk in China. The TRPV1 channel can be activated by capsaicin, acidic pH, and oxidative stress [12], while the TRPA1 channel can be activated by ROS such as superoxide, hydrogen peroxide (H2O2), and the products of lipid peroxidation [13]. Both channels can be activated by exogenous environmental irritants, such as diesel exhaust particles (DEP), ozone, cigarette smoke, and PMs [11]. We examined the importance and mechanism of TRPV1 and TRPA1 actions in the PM2.5-induced murine model of lung inflammation, AHR, and oxidative stress by administering AMG9810, a TRPV1 antagonist, and A967079, a TRPA1 antagonist, separately or in combination prior to PM2.5 instillation to mice
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