The Biological Mechanisms Behind Injury and Inflammation: How They Can Affect Treatment Strategy, Product Performance, and Healing

Nancy L. Parenteau, PhD; Janet Hardin-Young, PhD


Wounds. 2007;19(4):87-96. 

In This Article

The Innate Immune Response

Neutrophils are attracted to the wound site by the chemotactic molecular gradients formed by the release of chemokines and also by microbial peptides.[39,40] NF-kB, which plays a central role in inflammatory signaling is regulated not only by TNF-a and IL-1 and their associated receptors but also by the activation of toll-like receptors (TLR) that can be activated by both necrotic cells and by lipopolysaccharides (LPS) from bacterial cell walls.[41,42,43] Therefore, injury, contamination, and inflammation are linked not only by PAR but also by NF-kB. Just as PAR (and associated G-protein signaling) constitutes a signaling system for the activation of the injury component of the response, NF-kB constitutes the signaling system for the inflammatory component of the first phase of healing.

While activation of acute injury and inflammation responses are important to initiate healing, their resolution is important to progress to repair. The inability to adequately resolve one or both responses is a significant factor in chronic wound pathology. Macrophages, or activated monocytes recruited from the blood stream are an important cellular component to the resolution of inflammation. Indeed, studies have empirically established the presence and activity of macrophages to be an important component to positive healing.[13,44,45] While neutrophils are attracted to the wound within minutes, macrophages reach their highest number in the normal acute human wound on day 2.[17] Macrophages release a number of cytokines and growth factors into the wound site while limiting the proteolytic activity of neutrophil elastase. However, macrophages interact with neutrophils in additional ways that are important to the resolution of acute inflammation. Macrophages bind neutrophils and cause neutrophil apoptosis in conjunction with surface-bound TNF-a.[46,47,48] Phagocytosis of the apoptotic neutrophil by the macrophage then results in suppression of interleukin and prostaglandin production while increasing the production of TGF-b, a potent anti-inflammatory factor that effectively limits further release of pro-inflammatory cytokines. Macrophages prepare the area for wound granulation through:

  • Inflammatory cell clearance

  • Debris removal through phagocytosis

  • Initiation of granulation through the support of angiogenesis and fibroblast chemotaxis.

Inflammatory cell clearance may be one of the most significant contributions of the macrophage since angiogenesis and fibroblast chemotaxis are also supported through the production of cytokines and factors produced by multiple sources in the wound environment ( Table 1 ). The timing and degree of neutrophil and macrophage activity will depend on the degree of contamination as well as the physiological and hormonal status of the individual.[45] In elderly patients, there is a natural decline in the adrenal estrogenic precursor dehydroepiandrosterone (DHEA). Estrogen hormones normally dampen the inflammatory response and support additional aspects of healing in part, by limiting the activity of macrophage migration inhibitory factor (MIF).[49] The decline of DHEA and estrogen leads to increased MIF, resulting in enhanced inflammation and poorer healing.[50] In elderly men, the effects of increased MIF are exacerbated by the presence of testosterone.[51]


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