Abstract

Many ARDS survivors have evidence of pulmonary fibrosis after ARDS clinical resolution. A clinically relevant animal model is essential for assessing disease progression, since most ALI models using LPS do not evolve with persistent inflammation, limiting the understanding of which factors determine adequate repair or progression to fibrosis in the advanced stages of the disease. In this study, we proposed a model of ALI that associates LPS with high O2 concentration, aimed to induce a severe pulmonary lesion with chronic evolution to lung fibrosis. Mice were divided into 6 groups: CTR-4h, CTR-3w, LPS-4h, LPS-3w, LPS+O2-4h and LPS+O2-3w. LPS groups received 200µg of LPS IT and were euthanized after 4 hours or 3 weeks. LPS+O2 groups received 200µg of LPS IT+72 hours of O2 80% and were euthanized after 4 hours or 3 weeks. We analyzed lung tissue inflammation, pulmonary cytokine levels in BALF, the expression of pulmonary SOD-2 activity, and the deposition of collagen and elastic fibers in the pulmonary parenchyma. The LPS ALI model showed high number of neutrophils in lung tissue, and high levels of IL-6, KC and TNF in BALF in the LPS-4h group, and  high levels of IL-4 and TGF-ß in the LPS-3w group. Parenchymal remodeling was not observed in the LPS groups. The LPS+O2 ALI model showed high number of neutrophils and high levels of IL-6 and IL-10 in both 4h and 3w groups, high levels of IL-1ß and KC in LPS+O2-4h group, high expression of SOD-2 in both 4h and 3w groups, and high content of collagen and elastic fibers in lung tissue in the LPS+O2-3w group.  Our results show that the LPS+O2 model induced an acute lung injury with persistent pulmonary inflammation and remodeling after 3 weeks. Funding: CAPES, CNPq.