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230 HIV-1 TRANSGENIC EXPRESSION IN RATS IMPAIRS ALVEOLAR EPITHELIAL BARRIER FUNCTION.
  1. C. C. Lassiter,
  2. P. C. Joshi,
  3. L. A.S. Brown,
  4. D. M. Guidot
  1. Atlanta VAMC and Emory University, Atlanta, GA

Abstract

The worldwide propagation of the human immunodeficiency virus (HIV) is one of our most challenging medical dilemmas. This highly mutable virus causes widespread immune dysfunction, predisposing its host to pulmonary oxidative stress and opportunistic infections that can lead to respiratory failure and death. However, the precise mechanisms leading to increased oxidative stress and infection are incompletely defined, and although the effects of HIV-1 on alveolar macrophage function have been studied extensively, very little attention has focused on the effects of HIV-1 expression on alveolar epithelial function. We hypothesized that expression of the HIV-1 genome causes oxidative stress within the alveolar space and impairs alveolar epithelial barrier function. To test our hypothesis, we used an HIV-1 transgenic rat model that expresses the HIV-1-related proteins but is not infected with virus. To evaluate HIV-1-induced oxidative stress, we determined the levels of glutathione (GSH) by HPLC in the lung lavage fluid of HIV-1 transgenic vs wild-type rats. To evaluate epithelial barrier function, we assessed both alveolar epithelial monolayer integrity using radiolabeled inulin and sucrose permeability in vitro and lung liquid clearance of an intratracheal saline challenge in vivo. We determined that HIV-1 expression decreased lung lavage GSH levels by more than 60% (p < .05). In parallel, epithelial monolayers from HIV-1 transgenic rats were {223}200% (p < .05) more permeable than epithelial monolayers from wild-type rats. Finally, HIV-1 animals had an {223}25% decrease (p = .07) in liquid clearance in vivo compared to wild-type rats. In conclusion, transgenic expression of the HIV-1 genome in rats impairs alveolar epithelial barrier function. We speculate that alveolar epithelial barrier dysfunction contributes to respiratory failure in HIV-1-infected individuals when they develop serious pulmonary infections. Therefore, the respiratory failure that often accompanies Pneumocystis infection and other pneumonias in HIV-1-infected individuals may reflect underlying alveolar epithelial dysfunction and not simply overwhelming infection. If this is true, then treatments aimed at preserving and/or restoring alveolar epithelial barrier function could potentially decrease the incidence and/or severity of respiratory failure in these uniquely susceptible individuals.

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