Tanshinone ⅡA Inhibits Alveolar Macrophage Polarization, Inflammation and Mitochondrial Damage by Regulating the PAPR-1 Signaling Pathway.

Background: Alveolar macrophages (AMs) play a pivotal role in the initiation, resolution, and tissue repair processes of pulmonary inflammatory diseases. The regulation of poly (ADP-ribose) polymerase-1 (PARP-1) is closely associated with inflammatory mechanisms, including the expression of inflammatory mediators, macrophage polarization, and mitochondrial damage. Tanshinone IIA, the primary active component of the Chinese herb Objectives: This study aims to elucidate the mechanism by which tanshinone IIA inhibits macrophage polarization, attenuates the inflammatory response, and prevents mitochondrial damage through regulation of the PARP-1 signaling pathway. Methods: We investigated the effects of tanshinone IIA on macrophage polarization, inhibition of inflammation and oxidative stress, and protection against mitochondrial damage via the PARP-1 signaling pathway using various experimental approaches, including enzyme-linked immunosorbent assay (ELISA), flow cytometry, western blot analysis, molecular docking, and molecular dynamics (MD) simulation studies. Results: Compared with the model group, tanshinone IIA significantly inhibited the phosphorylation and activation of nuclear factor kappa B (NF-κB, P < 0.05) in AMs by modulating PARP-1 (P < 0.05). This modulation led to suppression of NLRP3 inflammasome activation (P < 0.05 versus the model group), ultimately inhibiting the release of inflammatory mediators such as nitric oxide (NO), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α, P < 0.05). Simultaneously, tanshinone IIA suppressed cellular oxidative stress via the Nrf2/heme oxygenase-1 (HO-1) pathway (P < 0.05 versus the model group), resulting in decreased reactive oxygen species (ROS) release (P < 0.05) and reduced mitochondrial MitoSOX production (P < 0.05). By regulating PARP-1, tanshinone IIA also effectively inhibited mitochondrial damage (compared with the model group, JC-1 decreased and mitochondrial permeability transition (MPTP) increased, P < 0.05) and M1 polarization of AMs induced by lipopolysaccharide [LPS; expression of CD86, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) decreased; arginase-1 (ARG-1) and CD206 increased, P < 0.05]. Furthermore, it efficiently modulated signaling pathways involved in mitochondrial fission and fusion [optic atrophy 1 (OPA1), dynamin-related protein 1 (DRP1)] (P < 0.05). Conclusions: These findings suggest that the therapeutic effects of tanshinone IIA on pulmonary inflammation are closely related to its ability to inhibit inflammatory damage and oxidative stress, regulate AM polarization, and alleviate mitochondrial damage in AMs through modulation of the PARP-1 pathway.