Abstract
Macrophages play essential roles in the generation and resolution of inflammation. Ischemia-reperfusion injury (IRI) triggers a systemic inflammatory response and leads to cellular injury and organ failure. During surgical procedures of the liver, such as hepatic resection and liver transplantation, IRI leads to the dysfunction of the liver. Rho-associated protein kinase (ROCK) inhibitors were reported protecting the liver from IRI. However, the systematic administration of ROCK inhibitors causes severe hypotension. Here, using Fasudil carried liposomes, we specifically inhibited the ROCK-II expression in Kupffer cells and blood monocytes. Through this macrophage/monocyte specific treatment of Fasudil, we successfully protected the liver from IRI by shifting Kupffer cells/monocytes from M1/classical to M2/patrolling phenotype in the liver and peripheral blood. Our finding provides novel insights into the macrophage/monocyte-specific drug delivery and the treatment of liver IRI.
Highlights
Ischemia-reperfusion injury (IRI) is one of the most critical complications commonly associated with liver surgery [1], such as hepatic resection and liver transplantation
Macrophages/monocytes were targeted by Fasudil carried liposomes To realize the macrophage/monocyte specific targeting, we packaged Fasudil (Figure 1A) together with fluorescence indicator Alexa Fluor® 488 (AF488) into lipid bilayer liposomes, which has been widely used in the drug delivery for macrophage/monocyte [23,26]
From flow cytometry dot plots of peripheral blood leukocytes (CD45+, Figure 1F), most AF488+ cells were monocytes (CD115+, 80.85 ± 3.38 %, Figure 1G) and most monocytes were targeted (AF488+, 90.95 ± 3.40 %, Figure 1H). These results demonstrated the good efficiency and specificity of the macrophage/monocyte specific drug delivery by the Fasudil/AF488 carried liposomes
Summary
Ischemia-reperfusion injury (IRI) is one of the most critical complications commonly associated with liver surgery [1], such as hepatic resection and liver transplantation. Recent studies showed that there are at least two types of macrophages or monocytes, M1 and M2 macrophages [6] or classical/inflammatory and patrolling/regulatory monocytes [7], respectively. M1 macrophages are the “killer” type macrophages, which promote inflammation and rapidly eliminate the pathogens and cause tissue damage. The systematic administration of Fasudil was reported protecting mice from experimental autoimmune encephalomyelitis (EAE) and shifting macrophages from M1 to M2 [19]. Enhanced M2 macrophage polarization was reported to protect the liver from IRI [20]. In this study, we packaged Fasudil in liposomes to realize the specific targeting to macrophages/monocytes.
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