Pulmonary toxicity and fibrogenic response of carbon nanotubes

Abstract

Carbon nanotubes (CNTs) have been a subject of intensive research for a wide range of applications. However, because of their extremely small size and light weight, CNTs are readily inhaled into human lungs resulting in increased rates of pulmonary disorders, most notably fibrosis. Several studies have demonstrated the fibrogenic effects of CNTs given their ability to translocate into the surrounding areas in the lung causing granulomatous lesions and interstitial and sub-pleural fibrosis. However, the mechanisms underlying the disease process remain obscure due to the lack of understanding of the cellular interactions and molecular targets involved. Interestingly, certain physicochemical properties of CNTs have been shown to affect their respiratory toxicity, thereby becoming significant determinants of fibrogenesis. CNT-induced fibrosis involves a multitude of cell types and is characterized by the early onset of inflammation, oxidative stress and accumulation of extracellular matrix. Increased reactive oxygen species activate various cytokine/growth factor signaling cascades resulting in increased expression of inflammatory and fibrotic genes. Profibrotic growth factors and cytokines contribute directly to fibroblast proliferation and collagen production. Given the role of multiple players during the pathogenesis of CNT-induced fibrosis, the objective of this review is to summarize the key findings and discuss major cellular and molecular events governing pulmonary fibrosis. We also discuss the physicochemical properties of CNTs and their effects on pulmonary toxicities as well as various biological factors contributing to the development of fibrosis.

Figure 1

Mechanisms of lung fibrosis: irritants such as nanoparticles induce epithelial injury resulting in infiltration of immune cells such as neutrophils, eosinophils and alveolar macrophages at the site of tissue injury. Activated neutrophils can exaggerate the ROS response. Moreover, ROS generation upon particle–cell interactions activates cytokine growth receptor cascade. ROS-dependent activation of RTKs, MAPK, Akt and NF-κB results in expression of genes related to inflammation and fibrosis. ROS can also activate TGF-β to mediate the fibrogenic effects. Recruitment of leukocytes induces key pro-fibrotic cytokines including TNF-α, IL-1β and IL-13, which can further damage the epithelial cells. TNF-α and IL-1β stimulation upregulates TGF-β and PDGF, respectively, which in turn increase collagen production via fibroblast and myofibroblast proliferation. Alternatively, fibroblasts can directly induce fibrosis via proliferation and differentiation into myofibroblasts. In addition, epithelial cells undergoing EMT expand the pool of fibroblasts and myofibroblasts thereby driving fibrogenesis.