Table 1.

Immune cells involved in the detection, integration and healing following localized sterile injury.

Type	Tissue location	Main functions
Macrophages	Resident	Macrophages are innate immune cells that ingest and process foreign materials, dead cells, and debris and recruit additional macrophages in response to inflammatory signals. Tissue-resident macrophages include brain (microglial), muscle, gut, kidney, alveolar, liver (Kupffer cells), bone (osteoclasts), and interstitial connective tissue (histiocytes) macrophages. Resident macrophages produce cytokines, chemokines, proteases, nitric oxide, and leukotrienes as part of their damage detection and amplification roles to local injury. Blunting the activation of resident macrophages/immune cells may reduce the stress response to surgery.
Mast cells	Resident	Mast cells are densely granulated effector cells of inflammation and immunity. They are located close to outer layers and barriers, such as epithelial borders, nerves, mucosal membranes, and vascular walls. At a nerve lesion, mast cells degranulate and release histamine, prostaglandins, leukotrienes, chemokines, and cytokines (TnF-alpha) to initiate the neuropathic and nociceptive pain response. Mast cells are involved in the local inflammatory response, vasodilatation, and plasma extravasation.
Dendritic cells	Resident	Like macrophages, dendritic cells are mononuclear phagocytes with multiple subpopulations that orchestrate host defense and wound healing to resolve local inflammation and support the resolution of fibrosis. An overexpression of inflammation causes increased recruitment of dendritic cells and collateral local and systemic injury.
Fibroblasts	Resident	Fibroblasts are involved in remodeling of extracellular matrix after injury. Excessive proliferation or secretion of extracellular matrix proteins may result from an overexpression of inflammation and pathologic progression of fibrosis and further tissue injury and adhesions.
Neutrophil	Blood-borne	Neutrophils migrate from postcapillary venules into the site of sterile tissue injury (or infection) and are the hallmarks of endothelial activation and acute inflammation. Their entry into the cell and release of cytokines, chemokines, proteases, and oxidants can contribute to further damage. Neutrophils can also promote fibroblast proliferation, aberrant collagen accumulation, and fibrosis. Inhibition of neutrophils and neutrophil-platelet interactions may be an important and effective target to reduce the local stress response during surgery.
Monocytes	Blood-borne	Increased monocyte reactivity occurs in trauma, infection, or burns. During local tissue damage monocytes are rapidly recruited to the tissue usually after neutrophils, where they differentiate into and replenish tissue macrophages or dendritic cells. Monocytes are equipped with a set of Toll-like receptors and possess unique scavenger receptors that recognize damage or pathogen-associated molecular patterns (DAMPS and PAMPS) and can clear apoptotic neutrophils by phagocytosis in a non-inflammatory process called efferocytosis.
Lymphocytes (B cells, natural killer cells and T cells)	Resident (lymph) and blood-borne	Damaged or necrotic cells alert the immune system to activate naïve T cells even in the absence of infective pathogens. T-cell induction, specifically CD4+ (Helper) and CD8+ (cytotoxic) cells, is now known to participate in recruiting neutrophils for the initiation of wound healing after sterile injury. Lymphocyte cells can also contribute to further inflammation and induce the up-regulation of endothelial cell adhesion molecules. The gut is a major source of lymphocytes and one of the “drivers” of major organ dysfunction and failure during the stress response to surgery.