Activated fibroblasts and M2-polarized macrophages may contribute to the progression of pulmonary fibrosis by forming a positive feedback loop. This study was aimed to investigate whether fibroblasts and macrophages form this loop by secreting SDF-1 and TGF-beta and the impacts of neotuberostemonine (NTS) and tuberostemonine (TS). Mice were intratracheally injected with 3 U.kg(-1) bleomycin and orally administered with 30 mg.kg(-1) NTS or TS. Primary pulmonary fibroblasts (PFBs) and MH-S cells (alveolar macrophages) were used in vitro. The animal experiments showed that NTS and TS improved fibrosis related indicators, inhibited fibroblast activation and macrophage M2 polarization, and reduced the levels of TGF-beta and SDF-1 in alveolar lavage fluid. Cell experiments showed that TGF-beta1 may activated fibroblasts into myofibroblasts secreting SDF-1 by activating the PI3K/AKT/HIF-1alpha and PI3K/PAK/RAF/ERK/HIF-1alpha pathways. It was also found for the first time that SDF-1 was able to directly polarize macrophages into M2 phenotype secreting TGF-beta through the same pathways as mentioned above. Moreover, the results of the cell coculture confirmed that fibroblasts and macrophages actually developed a feedback loop to promote fibrosis, and the secretion of TGF-beta and SDF-1 was crucial for maintaining this loop. NTS and TS may disturb this loop through inhibiting both the PI3K/AKT/HIF-1alpha and PI3K/PAK/RAF/ERK/HIF-1alpha pathways to improve pulmonary fibrosis. NTS and TS are stereoisomeric alkaloids with pyrrole[1,2-a]azapine skeleton, and their effect on improving pulmonary fibrosis may be largely attributed to their parent nucleus. Moreover, this study found that inhibition of both the AKT and ERK pathways is essential for maximizing the improvement of pulmonary fibrosis. CI - Copyright (c) 2023 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.