Morris, Jodie L., McEwen, Peter C., Letson, Hayley L., and Dobson, Geoffrey P. (2023) Adenosine, Lidocaine and Magnesium (ALM) therapy modulates early sex-specific inflammatory and immune responses following experimental anterior cruciate ligament rupture and reconstruction. Translational Medicine Communications, 8. 14.

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Abstract

Background: Early dysregulation of local and systemic inflammatory and immune responses is implicated in the pathogenesis of fibrotic and degenerative complications after anterior cruciate ligament reconstruction (ACLR) surgery. In other surgical trauma models, ALM therapy has been shown to blunt inflammation, leading to a more permissive healing environment in injured tissues. The purpose of this study was to evaluate sex-specific effects of surgery and perioperative ALM therapy on leukocyte mobilization and activation, and systemic and joint tissue inflammation in a rat model of ACL rupture and reconstruction.

Methods: Adult male and female Sprague–Dawley rats were randomly divided into ALM (male, n = 15; female, n = 14) or Saline control (male, n = 13; female, n = 14) treatment groups. Three days after non-invasive ACL rupture, ACLR surgery was performed on the injured knee. Animals received a 1 h perioperative IV ALM or saline drip, and a 0.1 ml IA bolus of ALM or saline, and were monitored to 120 h postoperative. Hematology, leukocyte immunophenotyping, plasma and synovial inflammatory mediator concentrations, and joint tissue histopathology and gene expression of inflammatory markers were assessed.

Results: Following ACLR surgery, plasma concentrations of inflammatory cytokines IL-6, TNF-α and IL-1β peaked later and at a higher magnitude in females compared to males, with ALM dampening this systemic inflammatory response. At 1 h postoperative, ALM boosted circulating B cell numbers in males and females, and decreased neutrophil activation in females. By 72 h, numbers of circulating T cells with immunoregulatory potential were increased in all ALM-treated animals compared to Saline controls, and corresponded to a significant reduction in synovial TNF-α concentrations within the operated knees. Sex-specific treatment differences were found in inflammatory and immune profiles in the synovial fluid and joint tissues. Inflammatory cell infiltration and gene expression of markers of inflammation (Nfκb, Nlrp3), cytoprotective responses (Nrf2), and angiogenesis (Vegf ) were increased in joint synovial tissue from ALM-treated males, compared to controls. In females, ALM treatment was associated with increased mononuclear cell recruitment, and expression of M2 macrophage marker (Arg1) in joint synovial tissue.

Item ID:	79299
Item Type:	Article (Research - C1)
ISSN:	2396-832X
Keywords:	anterior cruciate ligament; reconstruction surgery; adenosine; lidocaine; magnesium; inflammatory; immune; sex; repair
Copyright Information:	© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Funders:	US Department of Defense (USAMRAA)
Projects and Grants:	USAMRAA Award No. W81XWH-20–1-0931. Log No. OR190008
Date Deposited:	11 Jul 2023 02:30
FoR Codes:	32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320216 Orthopaedics @ 100%
SEO Codes:	20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 80% 20 HEALTH > 2001 Clinical health > 200102 Efficacy of medications @ 20%
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