Abstract
Macrophages and eosinophils that infiltrate the lung interstitium are active promoters of bleomycin (BLM)-induced pulmonary fibrosis. Leukocyte infiltration indicates disrupted barrier function in endothelial cells. The aims of this study were to investigate tight junctions (TJs) and their regulation of zonula occludens-1 (ZO-1) proteins in pulmonary microvascular endothelial cells (PMVECs) during BLM-induced pulmonary fibrosis and to compare the BLM model with the pneumococcus-induced pneumonia model of lung injury. The results revealed that the majority of PMVEC TJs were in an open state in BLM-treated tissue, where PMVEC paracellular permeability remained consistently higher than in controls. Macrophage accumulation in the lung interstitium was also significantly higher than in controls. Alteration of ZO-1 protein expression further supported the apparent disruption in PMVEC TJs in tissues from BLM-treated rats. These changes were markedly different from the concurrent changes in pneumococcus-infected rats. The findings suggest that changes in the ZO-1 proteins of PMVECs underlie the sustained disruption of TJs in BLM-treated animal models of pulmonary fibrosis. This dysfunction of paracellular barriers directly leads to the sustained infiltration of leukocytes and corresponding cytokine secretion, proliferation of fibroblasts, and progression of pulmonary fibrosis.
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