Abstract
MK2 activation by p38 MAPK selectively induces inflammation in various diseases. We determined if a MK2 inhibitor (MK2i), improves cornea wound healing by inhibiting inflammation caused by burning rat corneas with alkali. Our study, for the first time, demonstrated that MK2i inhibited alkali burn-induced MK2 activation as well as rises in inflammation based on: a) blunting rises in inflammatory index, inflammatory cell infiltration, ED1+ macrophage and PMN+ neutrophil infiltration; b) suppressing IL-6 and IL-1β gene expression along with those of macrophage inflammatory protein-1α (MIP-1α), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1); c) reducing angiogenic gene expression levels and neovascularization (NV) whereas anti-angiogenic PEDF levels increased. In addition, this study found that MK2i did not affect human corneal epithelial cell (HCEC) proliferation and migration and had no detectable side effects on ocular surface integrity. Taken together, MK2i selectively inhibited alkali burn-induced corneal inflammation by blocking MK2 activation, these effects have clinical relevance in the treatment of inflammation related ocular surface diseases.
Highlights
Mitogen-activated protein kinase–activated protein kinase-2 (MAPKAPK2 or MK2) is an intracellular serine/ threonine kinase substrate downstream from p38 mitogen-activated protein kinase (MAPK) and its activation by p38 is implicated in many inflammatory diseases including postoperative ileus, pancreatitis, atherosclerosis, rheumatoid arthritis and cancer[14,15,16,17,18,19]
Alkali exposure induced p38 MAPK and MK2 signaling activation was evaluated on day 7
Corneal alkali burning induces inflammation and inflammatory NV as well as fibrosis. These effects lead to opacification and visual impairment, which cannot be corrected by performing keratoplastic surgery unless these responses to injury are first resolved by rendering them self-limiting[12,31]
Summary
Mitogen-activated protein kinase–activated protein kinase-2 (MAPKAPK2 or MK2) is an intracellular serine/ threonine kinase substrate downstream from p38 mitogen-activated protein kinase (MAPK) and its activation by p38 is implicated in many inflammatory diseases including postoperative ileus, pancreatitis, atherosclerosis, rheumatoid arthritis and cancer[14,15,16,17,18,19]. It is an established drug target for treating many inflammatory diseases since its activation selectively induces the translation and increases stability of pro-inflammatory cytokine, chemokine and cell adhesion factor mRNA20–23. MK2 is a viable drug target for treating corneal wounds caused by alkali exposure
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
