Leyu Fang1,2,3,4, Lu Chen1,2,3,5, Min Song1,2,3,4, Juan He6, Lusha Zhang1,2,3,4, Chunxiao Li1,2,3,4, Qianyi Wang1,2,3,4, Wenjie Yang1,2,3,4, Wei Sun1,2,3,4, Yuze Leng1,2,3,4, Hong Shi1,2,3,5, Shaoxia Wang1,2,3,4, Xiumei Gao1,2,3,5, Hong Wang1,2,3,4. 1. State Key Laboratory of Component-based Chinese Medicine, Tianjin, China. 2. Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China. 3. Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin, China. 4. School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China. 5. Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China. 6. Buchang Pharmaceutical Co. Ltd., Xi'an, China.
Abstract
CONTEXT: Naoxintong (NXT), a prescribed traditional Chinese medicine, widely used in cerebrovascular and cardiovascular diseases, could be effective in diabetic wounds. OBJECTIVE: This study evaluates the wound healing activity of NXT by employing an excisional wound splinting model. MATERIALS AND METHODS: NXT was dissolved in saline and given daily by gavage. Wounds were induced at the dorsum of non-diabetic (db/+) and diabetic (db/db) mice and treated with saline or 700 mg/kg/d NXT for 16 days. Wound closure was measured every four days. Extracellular matrix (ECM) remodelling, collagen deposition, leukocyte infiltration and expression of Col-3, CK14, CXCL1, CXCL2, MPO, Ly6G, CD68, CCR7, CD206, p-JAK1, p-STAT3 and p-STAT6 was analysed. RESULTS: NXT significantly accelerated rate of wound closure increased from 70% to 84%, accompanied by up-regulation of collagen deposition and ECM at days 16 post-injury. Moreover, NXT alleviated neutrophil infiltration, accompanied by down-regulation of CXCL1 and CXCL2 mRNA expression. In addition, NXT markedly augmented neutrophil efferocytosis. In diabetic wounds, the levels of M1 marker gene (CCR7) increased, while M2 marker gene (CD206) decreased, demonstrating a pro-inflammatory shift. Application of NXT increased M2 macrophage phenotype in db/db mice. Mechanistically, NXT treatment increased expression level of p-STAT3 and p-STAT6 at days 3 post-injury, indicating NXT mediated macrophages towards M2 phenotype and alleviated inflammation in diabetic wounds by activation of STAT3 and STAT6. CONCLUSIONS: Our study provides evidence that NXT accelerates diabetic wound healing by attenuating inflammatory response, which provides an important basis for use of NXT in the treatment of chronic diabetic wound healing.
CONTEXT: Naoxintong (NXT), a prescribed traditional Chinese medicine, widely used in cerebrovascular and cardiovascular diseases, could be effective in diabetic wounds. OBJECTIVE: This study evaluates the wound healing activity of NXT by employing an excisional wound splinting model. MATERIALS AND METHODS: NXT was dissolved in saline and given daily by gavage. Wounds were induced at the dorsum of non-diabetic (db/+) and diabetic (db/db) mice and treated with saline or 700 mg/kg/d NXT for 16 days. Wound closure was measured every four days. Extracellular matrix (ECM) remodelling, collagen deposition, leukocyte infiltration and expression of Col-3, CK14, CXCL1, CXCL2, MPO, Ly6G, CD68, CCR7, CD206, p-JAK1, p-STAT3 and p-STAT6 was analysed. RESULTS: NXT significantly accelerated rate of wound closure increased from 70% to 84%, accompanied by up-regulation of collagen deposition and ECM at days 16 post-injury. Moreover, NXT alleviated neutrophil infiltration, accompanied by down-regulation of CXCL1 and CXCL2 mRNA expression. In addition, NXT markedly augmented neutrophil efferocytosis. In diabetic wounds, the levels of M1 marker gene (CCR7) increased, while M2 marker gene (CD206) decreased, demonstrating a pro-inflammatory shift. Application of NXT increased M2 macrophage phenotype in db/db mice. Mechanistically, NXT treatment increased expression level of p-STAT3 and p-STAT6 at days 3 post-injury, indicating NXT mediated macrophages towards M2 phenotype and alleviated inflammation in diabetic wounds by activation of STAT3 and STAT6. CONCLUSIONS: Our study provides evidence that NXT accelerates diabetic wound healing by attenuating inflammatory response, which provides an important basis for use of NXT in the treatment of chronic diabetic wound healing.
Authors: Jennifer M Felton; Christopher D Lucas; David A Dorward; Rodger Duffin; Tiina Kipari; Sonja Vermeren; Calum T Robb; Kenneth G MacLeod; Bryan Serrels; Jürgen Schwarze; Christopher Haslett; Ian Dransfield; Adriano G Rossi Journal: J Allergy Clin Immunol Date: 2018-02-08 Impact factor: 10.793