The PI3K/Akt, p38MAPK, and JAK2/STAT3 signaling pathways mediate the protection of SO2 against acute lung injury induced by limb ischemia/reperfusion in rats

Abstract

Sulfur dioxide (SO2) is naturally synthesized by glutamate-oxaloacetate transaminase (GOT) from L-cysteine in mammalian cells. We found that SO2 may have a protective effect on acute lung injury (ALI) induced by limb ischemia/reperfusion (I/R) in rats. The PI3K/Akt, p38MAPK, and JAK2/STAT3 pathways are crucial in cell signaling transduction. The present study aims to verify the role of SO2 on limb I/R-induced ALI, and investigate whether PI3K/Akt, p38MAPK, and JAK2/STAT3 pathways were involved, as well as the relationship among the three pathways; we used specific inhibitors (LY294002, SB03580, and Stattic) to block them, respectively. The experimental methods of Western, ELISA, TUNEL, etc., were used to test the results. In the I/R group, the parameters of lung injury (MDA, MPO, TUNEL, cytokines) increased significantly, but the administration of Na2SO3/NaHSO3 attenuated the damage in the lung. The Western results showed that the rat's lung exist expression of P-STAT3, P-AKT, and P-p38 proteins. After I/R, P-STAT3, P-Akt, and P-p38 proteins expression all increased. After using Na2SO3/NaHSO3, P-Akt, and P-p38 proteins expression increased, but P-STAT3 protein expression decreased. We also found a strange phenomenon; compared to the I/R + SO2 group, the administration of stattic, P-p38 protein expression showed no change, but P-Akt protein expression increased (p < 0.05). In conclusion, SO2 has a protective effect on rats with limb I/R-induced ALI. The JAK2/STAT3, PI3K/Akt, and p38MAPK pathways are likely all involved in the process, and the JAK2/STAT3 pathway may have an impact on the P13K/Akt pathway.

PD-1 up-regulation on CD4 + T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

“…This work demonstrates that PD-1 up-regulation is also profibrotic through its capacity to enhance STAT3 expression, leading to production of profibrotic cytokines, such as TGF-β and IL-17A. STATTIC inhibition of STAT3 has been shown to reduce collagen-1 content and connective tissue growth factor using the bleomycin murine model of pulmonary fibrosis (39–41). Furthermore, it has been previously demonstrated that genetic enhancement and ablation of STAT3 in the murine bleomycin model increase and reduce lung fibrosis, respectively (42).…”

Role of carbonyl sulfide in acute lung injury following limb ischemia/reperfusion in rats

“…Limb I/R-induced ALI animal models were performed the same as previously described in detail [7, 11]. The SD rats were anesthetized via ip administration of sodium pentobarbital (40 mg/kg body weight).…”

Lung ischemia reperfusion injury: the therapeutic role of dipeptidyl peptidase 4 inhibition

“…The phosphatidylinositol 3'-kinase (PI3K)/Akt pathway, Janus kinase 2/signal transducer and activator of transcription 3 (JAK/STAT3) pathway, and p38 mitogenactivated protein kinase (MAPK) pathway play pivotal roles in cell signal transduction, inflammation, stress, apoptosis, cell cycle, and cell growth (26). Akt is a serine/threonine kinase that acts downstream of PI3K.…”

“…Akt is a serine/threonine kinase that acts downstream of PI3K. Akt has a variety of functions in apoptosis, proliferation, and differentiation (26). Akt and MAPK activate redox-sensitive transcription factor NF-E2-related factor 2 (NrF2), which is essential for protection against oxidative stress in different forms of ALI.…”

“…In ventilator-induced lung injury (VILI) silencing of PI3K/Akt turned out to attenuate injury and to increase glutathione concentrations (8). MAPK activation can promote production of inflammatory cytokines (e.g., TNF-α, IL-8) in mononuclear macrophages, and mediate the activation of neutrophils (26). TNF-α regulates several important pro-inflammatory, damageinducing actions.…”