Microenvironmental Alterations in Carbon Nanotube-Induced Lung Inflammation and Fibrosis

Signaling Pathways Implicated in Carbon Nanotube-Induced Lung Inflammation

“…These findings markedly escalate the interest and significance of elucidating inflammation and fibrosis induced by CNT exposure in the lung. It is noticeable that similar to the scenarios observed in many chronic diseases, exemplified by idiopathic pulmonary fibrosis, liver fibrosis, and systemic sclerosis, inflammation and fibrosis in CNT-exposed lungs are demonstrated to mechanistically interact with each other through the activities of effector cells, soluble mediators, and ECM (10)(11)(12)(13)(14). In this regard, the time-and context-dependent activation, mode of action, and function of immune responses play critical roles in regulating the initiation and progression of inflammation and fibrosis in the lung during CNT exposure.…”

“…Inflammation and fibrosis in the lung are the most predominant pathological phenotypes in CNT-exposed experimental animals, concluded from numerous studies carried out in the past decade. In keeping with the accumulative findings achieved in this area, a number of recent review articles have summarized the progress in different aspects of CNT-induced lung inflammation and fibrosis (10,11,(14)(15)(16)(17). To avoid repetition, here the current knowledge on this topic is introduced concisely and comprehensively as background information (Figure 1).…”

“…Type 2 immune response is activated through the induction and functionalization of Th2 lymphocytes and alternatively activated M2 macrophages, which produce type 2 cytokines and mediators that function in suppressing acute inflammation and promoting Th2-driven type 2 inflammation and organ fibrosis. The fibrotic response is induced through the enriched and activated fibroblasts and myofibroblasts, which are fibrosis effector cells responsible for producing ECM proteins (10,14). Thereafter, acute inflammatory and fibrotic responses decline, but the chronic consequences develop (18,20).…”

“…CNTinduced lung fibrosis is featured with thickened alveolar septa, formation of fibrotic foci and epithelioid granulomas, enrichment and activation of fibroblasts and myofibroblasts, elevated expression of fibrosis marker proteins, excessive deposition of ECM, and lack of massive alveolar epithelial cell death (15). The chronic inflammation is known to implicate M2 macrophages, T lymphocytes, and the increased levels of certain pro-inflammatory and pro-fibrotic cytokines, chemokines, and growth factors; nevertheless, it awaits further analysis for its features, activities, and functions in CNT-exposed lungs (14). In aggregate, these observations demonstrate that immune system activation controls the initiation, progression, and maintenance of CNTtriggered lung inflammation, and meanwhile plays critical roles in promoting CNT-induced lung fibrosis through producing a variety of pro-fibrotic mediators.…”

“…Thus, the production of proinflammatory mediators by alveolar macrophages in CNT-exposed lungs may trigger the onset of inflammation. Third, CNTs can penetrate airway and alveolar epithelium to induce epithelial lesions, which result in increased production and secretion of alarmins by epithelial cells, in the lung (14). Among CNT-induced alarmins, HMGB1 promotes acute inflammation by increasing IL-1b secretion, whereas IL-25, IL-33, and TSLP may trigger the recruitment of type 2 immune cells leading to the activation of type 2 immune response, in CNT-exposed lungs.…”