**8. Role of hypoxia in activating inflammatory pathways such as interleukins, cytokines,** *NFk-B1*

Chemokines and cytokines are low-molecular-weight proteins produced mostly by lymphocytes and macrophages. As neurotransmitters and hormones, they mediate intracellular and extracellular interactions in an autocrine, endocrine, and paracrine manner. They regulate various biological activities, including local and systemic antiand pro-inflammation, chemotaxis, metabolism, cellular proliferation, and tissue repair, by adhering to certain cell surface receptors [50].

*HIF-1α* attenuates periapical inflammation and tissue destruction, resulting in downregulation of nuclear factor-kappa B (*NF-κB*) and gene expressions. These two substances also prevented macrophages from activating *NF-κB* and producing pro-inflammatory cytokines. Furthermore, stimulation of HIF-1 reduced lipopolysaccharide-stimulated macrophage differentiation into M1 cells, resulting in a higher ratio of M2 macrophages to M1 cells [51]. In another study, *HIF-2a* activation by pro-inflammatory cytokines increases iNOS expression and activity via the *NF-κB* pathway, resulting in nitric oxide (NO) production, which causes liver damage when generated in excess [52].

cAMP-mediated signalling pathways might be changed in the presence of HIF1A, causing inflammatory-like processes to worsen. Only in the presence of Ni-induced hypoxia-inducible factor 1 (*HIF1α*) does prostaglandin (*PGE2*) synergistically accelerate Ni-induced Interleukin (IL-8) production [53]. Elevated IL-13 expression can cause eosinophilia and pathologies such as excessive mucus production. IL-13 can activate genes in the hypoxia signalling pathway, producing CD73 (immunoinhibitory protein) on the cell surface [54].
