Abstract
Rationale. Matrix metalloproteinase-9 (MMP-9) expression is upregulated in alveolar macrophages (AM) of HIV1+ smokers who develop emphysema. Knowing that lung epithelial lining fluid (ELF) of HIV1+ smokers contains increased levels of inflammatory cytokines compared to HIV1− smokers, we hypothesized that upregulation of lung cytokines in HIV1+ smokers may be functionally related to increased MMP-9 expression. Methods. Cytokine arrays evaluated cytokine protein levels in ELF obtained from 5 groups of individuals: HIV1− healthy nonsmokers, HIV1− healthy smokers, HIV1− smokers with low diffusing capacity (DLCO), HIV1+ nonsmokers, and HIV1+ smokers with low DLCO. Results. Increased levels of the Th17 related cytokine IL-23 were found in HIV1− smokers with low DLCO and HIV1+ smokers and nonsmokers. Relative IL-23 gene expression was increased in AM of HIV1+ individuals, with greater expression in AM of HIV1+ smokers with low DLCO. Infection with HIV1 in vitro induced IL-23 expression in normal AM. IL-23 stimulation of AM/lymphocyte cocultures in vitro induced upregulation of MMP-9. Lung T lymphocytes express receptor IL-23R and interact with AM in order to upregulate MMP-9. Conclusion. This mechanism may contribute to the increased tissue destruction in the lungs of HIV1+ smokers and suggests that Th17 related inflammation may play a role.
Highlights
Survival of individuals infected with HIV1 has been dramatically improved since the introduction of highly active antiretroviral therapy (HAART), but this increased survival has been associated with the development of chronic disorders [1]
Based on recent studies demonstrating the importance of IL-23 and the Th17 immune response in the development of chronic obstructive pulmonary disease [13,14,15], their role in the progression of HIV-1 infection [16,17,18,19,20], and the effect of IL-23 on increased lung matrix metalloproteinases (MMPs)-9 in mice [21], we focused on a possible role of IL23 in the upregulation of MMP-9 in alveolar macrophages (AM) of HIV1+ smokers
In stark contrast to HIV1− nonsmokers or HIV1− healthy smokers, HIV1+ nonsmokers had detectible amounts of more than 2/3 of the cytokines represented on the array and more than twice as many compared to HIV1− healthy nonsmokers
Summary
Survival of individuals infected with HIV1 has been dramatically improved since the introduction of highly active antiretroviral therapy (HAART), but this increased survival has been associated with the development of chronic disorders [1]. In the context that lung epithelial lining fluid (ELF) of HIV1+ smokers has increased levels of a variety of cytokines [5, 7,8,9,10] and that several cytokines mediate the activation state of AM [11, 12], we hypothesized that, in the presence of cigarette smoke, upregulation of MMP-9 is associated with increased levels of proinflammatory cytokines and that their interplay may be contributing to the early development of emphysema in HIV1+ smokers. Assessment of inflammatory/immune cells recovered by lavage and lower respiratory tract ELF of HIV1− healthy nonsmokers, HIV1+ nonsmokers, HIV1− healthy smokers, HIV1− smokers with low DLCO and HIV1+ smokers with low ADMLCOindHeImVo+nssmtroatkeesrsthisatlitkheelyudperreigvuedla,taiot nleaosfttihnepMarMt, bPy-9AbMy
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