Clinical and experimental studies on inflammatory mediators during AIDS-associated Pneumocystis carinii pneumonia

This thesis is based on studies carried out during my appointment as a research fellow at the Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, Denmark from 1993 to 1997. Part of this period was spent as a guest researcher at the Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, USA. Pneumocystis carinii pneumonia (PCP) is the most frequent AIDS defining illness over the past 20 years. PCP is associated with considerable morbidity and mortality. An inflammatory reaction to P. carinii is believed to cause respiratory failure. This thesis has attempted to delineate important mechanisms of the inflammatory cascade, and to determine how inflammation is initiated during PCP. In histopathological studies of lung specimens it was shown that PCP caused significant inflammation and destruction of tissue. Specific pathological changes of the alveolar epithelium was observed in PCP but not for other HIV related lung diseases. By determining concentrations of soluble markers of immune activation we found that anti-microbial therapy exacerbated an ongoing inflammatory reaction. Adjuvant glucocorticosteroids suppressed levels of soluble immune markers. Bronchoalveolar lavage (BAL) neutrophilia has been associated with disease severity, and an increased risk of death from PCP. Through competitive inhibitory studies, we showed that BAL fluid neutrophil chemotactic activity largely was explained by the presence of interleukin-8 (IL-8). Further, we showed a correlation between high levels of BAL fluid IL-8 and mortality. Adjuvant treatment with glucocorticosteroids lowered BAL fluid IL-8 levels. In experimental studies we found that P. carinii Major Surface Antigen (MSG) induced IL-8 and tumor necrosis factor-alpha secretion from human monocytes and an alveolar epithelial cell line (A549). Binding of MSG to monocytes appeared to be mediated by mannose receptors, while A549 cells recognized MSG through mannose and glucan receptors. Glucocorticosteroids attenuated IL-8 secretion from A549 cells. These studies have confirmed that P. carinii infection induces tissue damage through a significant inflammatory response initiated by secretion of inflammatory mediators. Glucocorticosteroids attenuates the inflammatory response.