Tobacco and Antiretrovirals Modulate Transporter, Metabolic Enzyme, and Antioxidant Enzyme Expression and Function in Polarized Macrophages

Abstract

Background: Cigarette smoking increases systemic oxidative stress, inflammation, and viral replication in individuals with HIV. Macrophages are infected during HIV infection and serve as an important reservoir throughout the process. Macrophages exist in two phenotypes, the classically acti-vated M1 macrophage and alternatively activated M2 macrophage. The expression of drug efflux transporters and metabolic enzymes, which have direct effects on intracellular drug concentrations, differ between the pro-inflammatory M1 macrophage and the anti-inflammatory M2 macrophage. Objective: To further explain the role of tobacco use in worsened outcomes in the HIV + population receiving antiretroviral therapy. Methods: Western blotting was used to examine macrophage polarization and expression of drug efflux transporters, CYP enzymes, and antioxidant enzymes. The arginase assay was used to measure arginase activity. Cytokine production was measured using the human multiplex inflammatory cytokine assay kit. The 8-OHdG DNA Damage Quantification Direct Kit was used to quantify DNA damage. Viral replication under the influence of tobacco and antiretroviral drug use was measured by p24 Elisa. Results: We observed phenotypic shifts from M1 to M2 with both individual and combination treatments with cigarette smoke condensate and the protease inhibitor antiretroviral drug lopinavir. These shifts lead to changes in cytokine production, the expression of CYP enzymes, anti-oxidant enzymes, and drug efflux transporters, as well as changes in viral replication. Conclusion: This data suggest a mechanism by which tobacco use impairs HIV antiretroviral therapy to increase intracellular drug concentrations in this important cellular reservoir.

Differential packaging of inflammatory cytokines/ chemokines and oxidative stress modulators in U937 and U1 macrophages-derived extracellular vesicles upon exposure to tobacco constituents

“…Smoking/CSC is known to induce oxidative stress via the NF-κβ pathway [15,50]. Literatures have also established that smoking constituents/CSC induce oxidative stress via inducing CYPs, especially CYP2A6 and 1A1, which in turn metabolize smoking constituents in macrophages [12,14,51,52]. However, the lack of increased CYP packaging in EVs upon CSC exposure suggests that despite enhanced cellular expression of CYPs upon CSC exposure, CYP packaging in EVs is limited.…”

Improved Active Contour Snake Model for Hollow Filter Bar Roundness Inspection

“…Tobacco product quality is one of the important ways for tobacco companies to improve their market competitiveness; tobacco companies need to secure the overall quality of tobacco to gain a competitive advantage in the market, and the quality of tobacco products produced on line is often measured by the roundness index of tobacco flter rods [2]. Studies of smoke generation methods have shown that the roundness of cigarette flter rods directly afects the quality of cigarettes when the roundness error of the rods exceeds national standards [3]. In order to solve the problem of roundness error of cigarette flter rods, the study combined the characteristics of fuzzy flter rod images and introduced the improved active contour snake model.…”

Association between Smoking and Liver Fibrosis among Patients with Nonalcoholic Fatty Liver Disease

“…Smoking is a common poor living behavior in daily life. It can damage the antioxidant system [14, 15]. Although smoking can increase the risk for liver fibrosis and cirrhosis in patients with chronic hepatitis B (CHB) infection [16, 17], only a few studies have investigated the relationship between smoking and NAFLD.…”