Long term survival of lung transplantation is compromised by bronchiolitis obliterans (CBO). Other methods of inducing CBO, such as extended toxicant inhalation, produce histopathologic patterns seen with lung transplant CBO. Research has failed to discriminate early cellular markers that lead to CBO, which would provide clinical clues to disease progression. Our laboratory has produced both toxicant and transplant CBO models in the rat demonstrating small bronchiolar fibrosis preceded by peribronchiolar inflammation. We examined Eta-1 (Osteopontin) in these models, assessing this cytokine signal in order to identify the cellular correlate of the basic pathophysiologic mechanisms involved. Eta-1, a cytokine secreted by activated T lymphocytes, is reported to recruit and activate pulmonary macrophages, and could be an important mediator in CBO.
Rat models of inbred-mismatch tracheal transplant CBO were tested by whole lung BAL at 7 and 42 days. Toxicant-induced CBO (papaverine) was instituted in oubred SD rats by osmotic intratracheal pump delivery. Whole lung BAL was performed at 7 and 28 days. BAL from an intratracheal ARDS model was measured as control. Rat Eta-1 was measured by ELISA.
Eta-1 was significantly elevated in toxicant-induced CBO at 7 days (p<0.02 ANOVA), with little chronic reactivity. Transplant-induced CBO exhibited no upregulation of Eta-1 in BAL at 7 or 42 days. The ARDS model demonstrated off-scale high Eta-1 at 7 and 14 days, disappearing by day 28, when chronic fibrosis begins.
Early differences in BAL Eta-1 in the two CBO models suggest pathway differences to a similar final endpoint. Eta-1 has been reported in delayed-type immune responses early and in autoimmunity late. It appears to be neutrophil independent, but IL-12 related. These data suggest that a unique set of cell-mediated inflammatory cells and cytokines participate in early toxicant-induced CBO. Eta-1 could be useful in predicting CBO development.
Markers of specific pathways to bronchial damage could be of immense importance to the early diagnosis of toxicant CBO. Further investigation continues to elucidate early immunologic markers of transplant induced CBO.
J.A. Svetlecic, None.