Collagenases and the serine proteinases elastase and cathepsin G in steroid-induced Pneumocystis carinii pneumonia

Abstract

Pneumocystis carinii pneumonia (PCP) is characterized by the formation of leaky alveoli and a foamy alveolar exudate. To induce PCP, male Wistar rats were immunosuppressed by oral dexamethasone treatment for 12 weeks, during which time all rats developed PCP. Bronchoalveolar lavage fluid (BALF) was analyzed at that time and at 1, 2, and 4 weeks after the cessation of dexamethasone treatment, during which time the rats were recovering from PCP and immunosuppression (and was compared with the BALF obtained from healthy control rats), for type IV collagenase, elastase, cathepsin G, and collagenase activities. Scores for 72-kDa (matrix metalloproteinase type 2 [MMP-2]) and 92-kDa (MMP-9) type IV collagenase-gelatinase activities correlated with those for BALF macrophages (r ‫؍‬ 0.58; P < 0.001) and neutrophils (r ‫؍‬ 0.66; P < 0.001), respectively, suggesting that they may, in part, be derived from these cells. However, MMP-2 was constitutively expressed and may play a role in normal tissue remodeling. MMP-9 activity was highest in the group with PCP (1.8 ؎ 0.37; P > 0.05), with a gradual decline (1.0 ؎ 0.48 by week 4; P > 0.05) toward normal (0.67 ؎ 0.42) during recovery, which suggests a role for it in tissue-destructive inflammatory events. In rats with PCP the endogenously active collagenase was present at high levels compared with those in healthy controls (2.6 ؎ 0.69 versus 0.17 ؎ 0.17, respectively; P < 0.01), but they returned to normal by week 4 of recovery (0.42 ؎ 0.30; P > 0.05). Collagenase activity showed a correlation with cyst number (r ‫؍‬ 0.57; P < 0.001). The BALF of rats with PCP also contained the serine proteinases, which may act as pro-MMP activators. Ultramorphology disclosed increased pinocytotic activities, subepithelial bleb formation, and degeneration and denudation of the basal lamina. These findings suggest that the increased activities of collagenases in BALF caused by the host response against P. carinii might contribute to leaky alveoli.

Role of Pneumocystis jirovecii infection in chronic obstructive pulmonary disease progression in an immunosuppressed rat Pneumocystis pneumonia model

“…In addition, gelatin zymography assay revealed that MMP-2 and MMP-9 activity was increased in PCP model rats. Therefore, it was hypothesized that P. jirovecii infection may lead to the release of endogenous proteases which is in accordance with the literature (6,(35)(36)(37). In addition, upregulated levels of MMPs suggested that the occurrence and progression of emphysema may be caused by P. jirovecii colonization due to release of endogenous proteases and stimulation of protease release in the lung tissue of PCP model rats which is in agreement with a previous study (38) Similar upregulation of MMP levels have also been previously reported in COPD rats (33).…”

Matrix metalloproteinases‐I, ‐3 and ‐8 and myeloperoxidase in saliva of patients with human immunodeficiency virus infection

“…MMP-1 and MMP-3, which may originate from fibroblasts, monocytes/macrophages and epithelial cells, have not been identified in significant amounts in oral fluids (Birkedal-Hansen, 1993). Furthermore, in a recent rat model study of Pizeriinocystis cariiiii, collagenase activity in bronchoalveolar lavage (BAL) fluid was found to exist to a significant extent in endogenously active form (Sukura et al, 1995), and among the 56 HIV-seropositive in this study 10 patients were suffering from Pneumocystis cwiizii. In HIV-seropositive patients with opportunistic infections, expecially lung infections, increased neutrophil numbers and activities have been found to be associated with a fatal outcome (Sukura rt d, 1995).…”

Naturally acquired Pneumocystis carinii pneumonia in gene disruption mutant mice: roles of distinct T-cell populations in infection

“…(ii) Pulmonary accumulation of foamy honeycomb material was more abundant in diseased RAG-1 Ϫ/Ϫ mutants than in the other two mouse strains. This alveolar exudate is composed of proteinaceous material leaking through damaged alveolus-capillary boundaries under direct and/or indirect influence of the parasite (19,32,42). The finding of fewer intra-alveolar parasites in combination with a lower degree of alveolar damage supports our assumption.…”