Abstract
Swine pneumonia is a great threat for pig industry around the world, which is usually accompanied with neutrophils infiltration in the airway. Although interleukin-8 (CXCL8) and its receptors, CXC chemokine receptor 1 and 2 (CXCR1/2) in human have been well documented, the expression and function of CXCR1/2 is still unknown in swine. To explore the feasibility to develop new veterinary anti-inflammatory drugs targeting porcine CXCR1/2, we detected CXCR1/2 expression in swine pneumonia through Real-Time PCR and immunohistochemistry for the first time. Two porcine CXCR1/2 antagonists, CXCL8(3–72)N11R/G31P (pN11R) and CXCL8(3–72)G31P (pG31P) were prepared and their anti-inflammatory effects were evaluated using cell chemotaxis assays and animal experiments. Our data showed that CXCR1/2 expression, which was closely related to neutrophil infiltration in the lung, was significantly up-regulated in swine pneumonia. The pN11R and pG31P could effectively inhibit the directional migration of neutrophils in vitro. In vivo data also indicated that both pN11R and pG31P significantly relieved LPS-induced pneumonia in mice through decreasing the expression of TNF-α, CXCL8, and IL-1β, and inhibiting neutrophil influx into the lung. pG31P was more efficient. Our study suggested that it is possible to develop new veterinary anti-inflammatory drugs targeting porcine CXCR1/2, and pG31P is a promising candidate.
Highlights
The pig industry around the word has been suffering from respiratory diseases, especially pneumonia, which caused increasing mortality and decreasing production performance[1]
The results revealed that the expression of CXC chemokine receptor 1 and 2 (CXCR1/2) in swine pneumonia were up-regulated
Bronchopneumonia, suppurative pneumonia and serous pneumonia belong to exudative pneumonia, which are mainly generated by bacterial infections or mixed infections and characterized by increasing neutrophils www.nature.com/scientificreports
Summary
The pig industry around the word has been suffering from respiratory diseases, especially pneumonia, which caused increasing mortality and decreasing production performance[1]. It is urgent to develop a broad-spectrum, less residual anti-inflammatory drug for pneumonia treatment. During the past few decades, many antagonists target CXCL8-CXCR1/2, including Reparixin, SCH527123, SB22502 and CXCL8(3–73) K11R/G31P (hG31P) were developed[17,18,19,20,21]. SCH527123, 2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1(5-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobut-1-enylamino}benzamide, is an another allosteric antagonist of CXCR1/2, which could potently bind to CXCR1/2 and are difficult to dissociate, thereby inhibiting the interaction between CXCL1 or CXCL8 with CXCR1/2, affecting downstream signal transduction and controlling neutrophil infiltration[22,23]. We aimed to explore the relationship between CXCR1/2 and swine pneumonia, and developed a promising anti-inflammatory drug candidate targeting porcine CXCR1/2. Our study hopes to provides a new idea for swine anti-inflammatory drugs development
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