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Although the mechanism is unknown, people with HIV are at a markedly increased risk of emphysema. Matrix metalloproteinase-9 (MMP-9) has been implicated in non-HIV associated emphysema and it is elevated in the alveoli of people with HIV. Previously we determined that HIV transgene (HIV Tg) expression in a rat model significantly increases MMP-9 expression and activity. Further, we have determined that HIV suppresses antioxidant defenses and that MMP-9 activity is inversely related to antioxidant activity. We hypothesized that activation of Nrf2, the master transcription factor responsible for antioxidant defenses, would reverse HIV-induced increases in MMP-9 activity.​ ​ Methods: A rat alveolar macrophage cell line (NR8383) was treated with the transactivator of transcription (Tat, an HIV protein) with or without sulforaphane (SFP, a Nrf2 activator) for 24 hours prior to assessment of MMP-9 gene expression by RT-PCR. Primary alveolar macrophages (AMs) from HIV Tg rats and their littermate controls were treated with or without SFP ex vivo. Twenty-four hours later, expression of MMP-9 gene was assessed by RT-PCR. In parallel, cells were plated and treated with SFP for 48 hours before assessment of the receptor for advanced glycation end-products (RAGE) and MMP-9 by immunofluorescence.​ ​ Results: Tat exposure increased MMP-9 gene expression in NR8383 cells and SFP treatment significantly reduced those levels. MMP-9 protein was significantly increased and RAGE (an inverse surrogate for MMP-9 activity) was significantly decreased in HIV-1 Tg rat AMs. SFP treatment reduced MMP-9 activity (but not protein) to normal levels (as determined by a restoration of RAGE to wild-type levels).​ ​ Conclusions: Our data support the hypothesis that HIV-induced increases in MMP-9 activity are likely due, at least in part, to the suppression of antioxidant defenses by HIV proteins. Further work is needed to establish the relevance of this pathway in human subjects, but these studies offer the potential for an exciting new avenue of host-directed therapy for patients suffering from HIV-associated emphysema in the form of Nrf2 activation.

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