Pulmonary gelatinases in lung bronchiolitis models

Lung transplantation often yields morbidity and mortality through bronchiolitis obliterans syndrome (BOS) for which cause and cure are unknown. We have instituted both toxicant‐induced and transplantation‐induced BOS models to test immune hypotheses. Both models show classic airway collagen degradation with remodeling. The matrix metalloproteinase, MMP‐9, is activated in both models. We hypothesized that BOS involves MMP‐9 activation and remodeling through increase in TGF‐β and increased neutrophil activity. To test our hypothesis, MMP‐9 –latent, active, and lipocalin complexed—and TGF‐β were evaluated by zymography and ELISA in lung tissue and BAL. Toxicant‐induced BOS was initiated by osmotic pump tracheal instillation of papaverine for 30 days. Tracheas of DA inbred rats were implanted in (MHC mismatched) BBDR recipients to produce transplant BOS. Whole lung lavage and lung tissue were taken at 4 and 6 weeks. MMP‐9 (activated as percent of total) was significantly elevated (p=0.04)in both BOS models, but was more elevated in the transplant group. TGF‐β, proteolytically activated by surface MMP9, was moderately increased on BAL and tissue ELISA. Lipocalin‐related MMP‐9, the neutrophil‐bound enzyme, was greatly elevated in toxicant‐induced BOS, reflecting BAL cell counts. MMP9 tissue immunostaining corroborated the zymography and ELISA findings. Our BOS models show that transplant remodeling involves active MMP‐9 as a vital reactant in the TGF‐β pathway. Lung damage in toxicant‐induced BOS may also be mediated by neutrophil‐associated MMP‐9. Sponsor: UMKC Lung Res. Center