Abstract
Composite tissue injuries (CTI) are common among US Military Service members during combat operations, and carry a high potential of morbidity. Furthermore, CTI are often complicated due to an altered wound healing response, resulting in part from a dysregulation of the innate and adaptive immune responses. Unlike normal wound healing, in CTI, disruptions occur in innate immune responses, altering neutrophil functions, macrophage activation and polarization, further impacting the functions of T regulatory cells. Additionally, the biological underpinnings of these unfavorable wound healing conditions are multifactorial, including various processes, such as: ischemia, hypoxia, low nutrient levels, and altered cell metabolic pathways, among others, all of which are thought to trigger anergy in immune cells and destabilize adaptive immune responses. As a result, impaired wound healing is common in CTI. Herein, we review the altered innate and adaptive immune cells and their metabolic status and responses following CTI, and discuss the role a multi-pronged immunomodulatory approach may play in facilitating improved outcomes for afflicted patients.
Highlights
Composite tissue injuries (CTI) owing to high energy wounding mechanisms are an unfortunate reality of modern military combat operations
West et al (2012) showed an upregulation of TGF-β and macrophage colony stimulating factor (M-CSF) after a proinflammatory phase in CTI patients that helped in the differentiation of CD14hiCD16+, monocytes/macrophages, activated through C-reactive protein [58]
An example of how immune cells can be modulated to coordinate successful wound healing is provided by macrophages, in which staggered bolus release of IFN-γ and subsequent sustained release of IL-4 promote a shift from a proinflammatory to anti-inflammatory phenotype to mediate the scaffold vascularization [91]
Summary
Composite tissue injuries (CTI) owing to high energy wounding mechanisms (e.g., explosions, gunshot wounds) are an unfortunate reality of modern military combat operations. CTI are those injuries that involve significant damage to multiple tissues, including skeletal muscle, nerve, bone, vasculature, and dermal tissues [1,2,3,4] When such injuries affect the extremities, they often result in significant, long-term impairments in functional outcomes, and delay or prevent the service member from returning to duty. The immune-inflammatory response to acute injury is a highly complex system comprising multiple soluble (e.g., antibodies, complement) and cellular mediators (e.g., cytokines, prostaglandins) that serve to clear pathogens and cellular debris and stimulate tissue repair Speaking, this system is highly redundant with multiple compensatory signaling pathways in place to ensure that the initial inciting stimulus is neutralized and that the injury progresses towards an end-stage wound healing outcome from both a histological and functional perspective. The disrupted inflammation and immune response resulting from CTI, and the associated interactions within the site of injury, are broadly discussed as a means to highlight potential targets for immunomodulation to enhance wound healing
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