Objective:The progression of pulmonary fibrosis is a common clinical outcome issue after acute lung injury . This experiment constructed a model simulating clinical ALI-induced pulmonary fibrosis by repeatedly challenging with lipopolysaccharide and observed the development from acute lung injury to pulmonary fibrosis, exploring the possible mechanisms mediating the transition from inflammatory injury to fibrosis. Methods: Different doses of LPS (1, 2, 4, 8mg/kg) were administered intranasally to induce acute lung injury. At 7, 14, 21, 28, 35, and 42 days post-modeling, the expression of α-SMA and COI-1 in lung tissue, the content of hydroxyproline in lung tissue, and collagen fiber deposition in lung tissue observed by MASSON staining were compared to determine the process and degree of fibrosis formation in different modeling methods. The expression changes of IL-1β, TNF-α, and TGF-β1 in lung tissue at each time point were detected to explore the mechanisms of fibrosis formation. Results: The results showed that the M-1 group mice, which were hit with 1mg/kg, 4mg/kg, and 4mg/kg LPS for three consecutive days, could construct a stable ALI-induced pulmonary fibrosis model. MASSON staining results showed that the expression of α-SMA and COI-1, the content of hydroxyproline, and collagen fiber deposition in the lung tissue of M-1 group mice began to increase in a time-dependent manner after 7 days, with significant collagen deposition in the lung tissue interstitium at 21 days post-modeling, and fibrosis indicators significantly increased at 28 days, showing a significant difference compared to the Con group mice. MASSON staining results showed that collagen deposition continued to increase until the observed 42 days. In other model groups with different doses and different hit times, the HYP and collagen fibers in the lung tissue did not increase or increased insignificantly compared to the Con group mice. WB results showed that in the lung tissue of M-1 group mice, the transforming growth factor TGF-β1 began to gradually increase in expression 14 days after the hit, and was significantly higher than the Con group at 28 days. The pro-inflammatory cytokines TNF-α and IL-1β both significantly increased on the 7th day (acute phase), with TNF-α expression continuing to increase until the observed 28 days, while IL-1β gradually decreased after the acute phase on the 7th day. In other model groups that did not form fibrosis, the expression of TNF-α and IL-1β in the lung tissue both continued to decrease after the acute phase. Conclusion: LPS at doses of 1mg/kg, 4mg/kg, and 4mg/kg for three consecutive hits can successfully construct an ALI/ARDS-induced pulmonary fibrosis model, and its mechanism may mainly be related to the sustained high expression of TNF-α regulating TGF-β1 to induce fibroblast activation and proliferation.