Abstract
Despite the introduction of anti-retroviral therapy, chronic HIV infection is associated with an increased incidence of other comorbidities such as COPD. Based on the knowledge that binding of HIV to human airway basal stem/progenitor cells (BC) induces a destructive phenotype by increased MMP-9 expression through MAPK signaling pathways, we hypothesized that HIV induces the BC to express inflammatory mediators that contribute to the pathogenesis of emphysema. Our data demonstrate that airway BC isolated from HAART-treated HIV+ nonsmokers spontaneously release inflammatory mediators IL-8, IL-1β, ICAM-1 and GM-CSF. Similarly, exposure of normal BC to HIV in vitro up-regulates expression of the same inflammatory mediators. These HIV-BC derived mediators induce migration of alveolar macrophages (AM) and neutrophils and stimulate AM proliferation. This HIV-induced inflammatory phenotype likely contributes to lung inflammation in HIV+ individuals and provides explanation for the increased incidence of COPD in HIV+ individuals.
Highlights
Small airway BC from HIVand highly active anti-retroviral therapy (HAART)-treated HIV+ nonsmokers were isolated were plated on type IV collagen–coated 6-well and conditioned media were collected for cytokine assessment after 2 days
These findings provide evidence that small airway BC from HIV+ nonsmokers are induced in vivo to adapt an inflammatory phenotype
We focused on GM-CSF, IL-8, IL-1β and ICAM-1 as these mediators are relevant to chronic obstructive pulmonary disease (COPD) pathogenesis and are found at increased levels in epithelial lining fluid from HIV+ individuals[35,63] and HIV+ BC-conditioned media when cells were cultured ex vivo (Fig. 1A)
Summary
Small airway BC from HIVand HAART-treated HIV+ nonsmokers were isolated were plated on type IV collagen–coated 6-well and conditioned media were collected for cytokine assessment after 2 days. We focused on GM-CSF, IL-8, IL-1β and ICAM-1 as these mediators are relevant to COPD pathogenesis and are found at increased levels in epithelial lining fluid from HIV+ individuals[35,63] and HIV+ BC-conditioned media when cells were cultured ex vivo (Fig. 1A).
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