Silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction

Abstract

Background: Wide applications of nanoparticles (NPs) have raised increasing concerns about safety to humans. Oxidative stress and inflammation are extensively investigated as mechanisms for NPs-induced toxicity. Autophagy and lysosomal dysfunction are emerging molecular mechanisms. Inhalation is one of the main pathways of exposing humans to NPs, which has been reported to induce severe pulmonary inflammation. However, the underlying mechanisms and, more specifically, the interplays of above-mentioned mechanisms in NPs-induced pulmonary inflammation are still largely obscure. Considered that NPs exposure in modern society is often unavoidable, it is highly desirable to develop effective strategies that could help to prevent nanomaterials-induced pulmonary inflammation. Results: Pulmonary inflammation induced by intratracheal instillation of silica nanoparticles (SiNPs) in C57BL/6 mice was prevented by PJ34, a poly (ADP-ribose) polymerase (PARP) inhibitor. In human lung bronchial epithelial (BEAS-2B) cells, exposure to SiNPs reduced cell viability, and induced ROS generation, impairment in lysosome function and autophagic flux. Inhibition of ROS generation, PARP and TRPM2 channel suppressed SiNPs-induced lysosome impairment and autophagy dysfunction and consequent inflammatory responses. Consistently, SiNPs-induced pulmonary inflammation was prevented in TRPM2 deficient mice.

Nearly free surface silanols are the critical molecular moieties that initiate the toxicity of silica particles

“…Other studies in the past, including some of our investigations, proposed a mechanism of silica toxicity based on particleassociated radicals (e.g., silyl, siloxyl radicals) and ROS (e.g., hydroxyl, superoxide, and peroxyl radicals), the latter originating from the reaction with atmospheric components of dangling bonds upon fracture/grinding of the particles (64,65) or opening of strained three-membered siloxane rings (30). In some proinflammatory and profibrogenic cell-signaling pathways and transcription factor activation, the triggering role of particle ROS cannot be disregarded (66)(67)(68)(69), and they can contribute to increasing the oxidative stress in the lung milieu (20). The present data clearly document that particle ROS are not critical for membrane damage initiated by silica particles, as also shown in previous studies (45,(70)(71)(72).…”

TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions

“…As discussed above, the activity of nuclear PARP, particularly PARP-1, is crucial for the induction of ADPR generation and subsequent TRPM2 channel activation by ROS and other OS-inducing pathological stimuli. PARP inhibitors have been used in many studies as an alternative or additional means to prevent OS-induced TRPM2-mediated effects [ 36 , 39 , 48 , 74 , 75 , 82 , [121] , [122] , [123] , [124] , [125] , [126] ], including cell death. Example PARP inhibitors include SB-750139, N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide (PJ34), 3-aminobenzamide (3-AB) and 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ).…”

“…It is known that ER stress is an important indicator of pericyte dysfunction that can itself potentiate cellular damage and induce cell death via autophagy [ 157 , 158 ]. Increasing evidence suggests that ultrafine PMs with a size of <100 nm commonly present in polluted air and diverse NPs widely used in nanomaterials are potent in inducing OS [ 13 , 48 ], ER stress and autophagy-mediated cell death [ 159 , 160 ]. We have recently examined the role of the TRPM2 channel in mediating zinc oxide-NPs (ZnO-NPs)-induced OS, ER stress and autophagy in brain vascular pericytes [ 161 ].…”

“…The TRPM2 channel is widely distributed throughout the body and is highly sensitive to activation by OS-inducing stimuli [ [31] , [32] , [33] ]. A large number of studies have been carried out over the past decades that provide compelling evidence to show that the TRPM2 channel is a key mechanism mediating OS-induced alteration in intracellular Ca 2+ and Zn 2+ homeostasis to disrupt various cellular functions and further support a significant role for aberrant TRPM2 channel activity in diverse OS-associated pathologies [ [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] ]. A well-established mechanism, among others, by which the TRPM2 channel contributes to these pathological processes, is to mediate OS-induced cell death.…”

Silica Nanoparticles in Transmucosal Drug Delivery

“…Further studies on the safety in human, reproducibility, stability and scalability of the silica nanoparticles are expected. Numerous studies reported the toxicity profiles of silica nanoparticles in vitro cells or animal models [140][141][142][143][144][145]. However, to date, only one study confirmed that silica nanoparticles are safe in healthy humans [129].…”