General mechanisms of nicotine-induced fibrogenesis

Abstract

Cigarette smoking contributes to the development of cancer, and pathogenesis of other diseases. Many chemicals have been identified in cigarettes that have potent biological properties. Nicotine is especially known for its role in addiction and plays a role in other physiological effects of smoking and tobacco use. Recent studies have provided compelling evidence that, in addition to promoting cancer, nicotine also plays a pathogenic role in systems, such as the lung, kidney, heart, and liver. In many organ systems, nicotine modulates fibrosis by altering the functions of fibroblasts. Understanding the processes modulated by nicotine holds therapeutic potential and may guide future clinical and research decisions. This review discusses the role of nicotine in the general fibrogenic process that governs fibrosis and fibrosis-related diseases, focusing on the cellular mechanisms that have implications in multiple organ systems. Potential research directions for the management of nicotine-induced fibrosis, and potential clinical considerations with regard to nicotine-replacement therapy (NRT) are presented.

Figure 1.

Nicotine causes damage to epithelial cells. In various systems, nicotine has been shown either to directly cause damage to epithelial barriers or to potentiate the effects of injury. This results in increased release of inflammatory factors, expression of epithelial-mesenchymal transition (EMT) markers, and a change in ion homeostasis representative of epithelial dysfunction. In the lung and intestine, increased eosinophils accompany these changes.

Figure 2.

Nicotine-stimulated release of TGF-β1 and CTGF. Nicotine stimulates the release of TGF-β1 either directly or through the α7-nAChR. Nicotine is postulated to trigger TGF-β1 release in other cell types, such as hepatocytes and other epithelial cells, in a similar way.

Figure 3.

Nicotine stimulates neutrophilic functions in emphysema. Nicotine increases the recruitment of neutrophils to the alveolar space and release of granules.

Figure 4.

Proposed mechanisms for the production of ROS in various cells types. Nicotine causes epithelial cell damage that results in the production of ROS. Nicotine also triggers the production of ROS by the up-regulation of NADPH in macrophages. Nicotine causes increases in lipid peroxides and decreased GSH in fatty liver disease. Nicotine also triggers the production of ROS through injury and up-regulation of NADPH and NOX4 in mesangial cells. Nicotine is implicated in ROS generation in other cell types and future research directions. Overlap of these mechanisms (not shown) likely occurs. Some of these mechanisms (i.e., decreased GSH) are suspected in many systems.

Figure 5.

Nicotine increases collagen production through its actions on fibroblasts. Nicotine increases collagen production in fibroblasts and reduces the phagocytosis of collagen. Nicotine has a proliferative effect on fibroblasts. Nicotine stimulates the morphogenesis of fibroblasts into a myofibroblastic phenotype.