Delivery of the high-mobility group box 1 box A peptide using heparin in the acute lung injury animal models

Abstract

In this study, the efficacy of the high-mobility group box-1 box A (HMGB1A)/heparin complex was evaluated for the treatment of acute lung injury (ALI). HMGBIA is an antagonist against wild-type high-mobility group box-1 (wtHMGB1), a pro-inflammatory cytokine that is involved in ALls. HMGBIA has positive charges and can be captured in the mucus layer after intratracheal administration. To enhance the delivery and therapeutic efficiency of HMGBIA, the HMGBIA/heparin complex was produced using electrostatic interactions, with the expectation that the nano-sized complex with a negative surface charge could efficiently penetrate the mucus layer. Additionally, heparin itself had an anti-inflammatory effect. Complex formation with HMGBIA and heparin was confirmed by atomic force microscopy. The particle size and surface charge of the HMGB1A/heparin complex at a 1:1 weight ratio were 113 nm and 25 mV, respectively. Intratracheal administration of the complex was performed into an ALI animal model. The results showed that the HMGB1A,ffieparin complex reduced pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 beta, more effectively than HMGBIA or heparin alone. Hematoxylin and eosin staining confirmed the decreased inflammatory reaction in the lungs after delivery of the HMGB1A/heparin complex. In conclusion, the HMGB1Affieparin complex might be useful to treat ALI.