The MAPK‐activator protein‐1 signaling regulates changes in lung tissue of rat exposed to hypobaric hypoxia

Abstract

This study reports the role of MAPKs (JNK, ERK, and p38), and activator protein-1 (AP-1) transcription factor in the hypobaric hypoxia induced change in lung tissue. Healthy male Sprague-Dawley rats were exposed to hypobaric hypoxia for 6, 12, 24, 48, 72, and 120 hr. Hypoxia resulted in significant increase in reactive oxygen species (ROS), vascular endothelial growth factor (VEGF) and decreased nitric oxide (NO), these act as signaling molecules for activation of MAPK and also contribute in development of vascular leakage (an indicator of pulmonary edema) as confirmed by histological studies. Our results confirmed JNK activation as an immediate early response (peaked at 6-48 hr), activation of ERKs (peaked at 24-72 hr) and p38 (peaked at 72-120 hr) as a secondary response to hypoxia. The MAPK pathway up regulated its downstream targets phospho c-Jun (peaked at 6-120 hr), JunB (peaked at 24-120 hr) however, decreased c-Fos, and JunD levels. DNA binding activity also confirmed activation of AP-1 transcription factor in lung tissue under hypobaric hypoxia. Further, we analyzed the proliferative and inflammatory genes regulated by different subunits of AP-1 to explore its role in vascular leakage. Increased expression of cyclin D1 (peaked at 12-72 hr) and p16 level (peaked at 48-120 hr) were correlated to the activation of c-jun, c-Fos and JunB. Administration of NFκB inhibitor caffeic acid phenethyl ester (CAPE) and SP600125 (JNK inhibitor) had no effect on increased levels of Interferon-γ (IFN-γ), Interleukin-1 (IL-1), and Tumor Necrosis Factor-α (TNF-α) thereby confirming the involvement of AP-1 as well as NFκB in inflammation. Expression of c-jun, c-Fos were correlated with activation of proliferative genes and JunB, Fra-1 with pro-inflammatory cytokines. In conclusion immediate response to hypobaric hypoxia induced c-Jun:c-Fos subunits of AP-1; responsible for proliferation that might cause inhomogeneous vasoconstriction leading to vascular leakage and inflammation at increased duration of hypobaric hypoxia exposure.

Integrative analysis of miRNA–mRNA network in high altitude retinopathy by bioinformatics analysis

“…These miRNAs and mRNAs may play an important role in the development of HAR.FOS, consisting of c-Fos, FosB, Fra1 and Fra2[35], was significantly downregulated in our hypoxia-cultured HRMECs. In the lung tissues of hypoxic rats, the expression of c-Fos and FosB was significantly decreased[36], which is consistent with our results. C-Fos promotes the development of inflammatory diseases such as arthritis[37], but it also inhibits inflammation in myeloid and lymphoid cell lineages[38].…”

Transcriptome and Metabolome Integration Provides New Insights Into the Regulatory Networks of Tibetan Pig Alveolar Type II Epithelial Cells in Response to Hypoxia

“…Similar results have been found in periodontal ligament stem cells (He et al, 2016;Kabiri et al, 2018). Previous studies have shown that the sodium hydrosulfide-mediated inhibition of the cigarette smoke-induced phosphorylation of ERK, JNK and p38 MAPK may be a novel strategy for the treatment of chronic obstructive pulmonary fibrosis through the inhibition of inflammation, epithelial cell injury and apoptosis (Guan et al, 2020;Shologu et al, 2018;Singh et al, 2018). Therefore, we focused our further studies on MAPK signaling.…”

Scutellarin Prevents Angiogenesis in Diabetic Retinopathy by Downregulating VEGF/ERK/FAK/Src Pathway Signaling

“…The increased RI was indicative of distal vasoconstriction, such as constriction at the precapillary or capillary level that resulted in decreased blood flow in the retinal capillary bed, though the exact degree of blood flow reduction was not measured. A previous study reported that abnormal vasoconstriction caused by hypoxia occurs along with increases in VEGF [61] and inhibitors of the VEGF pathway have been regarded as promising therapeutic agents for relieving vasoconstriction [62]. To our surprise, oral administration of SCU in diabetic rats not only decreased retinal angiogenesis but also corrected abnormal vasoconstriction by inhibiting the expression of VEGF.…”