The role of apoptosis in wound healing

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Abstract

Wound healing involves a series of rapid increases in specific cell populations that prepare the wound for repair, deposit new matrices and finally, mature the wound. Upon completing their tasks, these specific cell types must be eliminated from the wound prior to the progression to the next phase of healing. The most logical method of cellular down-regulation is through apoptosis. Apoptosis allows for the eliminations of entire populations without tissue damage or an inflammatory response. This review discusses which cells dominate the various phases of tissue repair and how the cellular pattern may vary after differing types of injury. The potential mechanisms involved in the down-regulation of inflammation and fibrosis are also covered. The studies that support the hypothesis that apoptosis is involved in the regulation of wound healing are discussed. The evidence supporting potential cell signals involved in the induction of apoptosis in tissue repair are examined. Finally, the review ends with a presentation of how dysregulation of apoptosis can lead to pathologic forms of healing such as excessive scarring and fibrosis. By understanding the mechanisms controlling apoptosis and tissue repair, one may eventually develop therapeutic modalities to minimize scarring, a final pathway for many disease processes.

Section snippets

Cellular changes after wound healing

After injury a great variety of signals are released that not only initiate but regulate all aspects of tissue repair. For decades, histologic analyses revealed that there is a regular sequence of differing cell populations that appeared in an incisional wound (Fig. 1). The role of each different cell population has been investigated and currently a function for most types has been proposed. To determine the function of each population, specific cell types were eliminated to determine whether

Variations in the cellular pattern after injury

Most of the information regarding the phases of tissue repair were determined for incisional wounds. In other types of wounds, especially open wounds, the phases of tissue repair tend to blend together and can co-exist in different locations dependent on the degree of tissue repair. A spectrum of the various phases exists with the inflammatory phase being found in the central open areas while more mature phases are found as one travels towards the original wound edge (Fig. 2). There is

Down-regulation of inflammation and the healing process

A great deal of information is known about what `turns on' the inflammatory and fibroblastic responses, but little is known about what “turns off” inflammation and scar formation. All of the various cellular populations go through phases of rapid proliferation in processes that are tied to known signaling processes. What makes the cells disappear has not been a major focus of investigation. Cell populations must change in order to start the next phase of the healing process. For instance, if

Apoptosis as the method of cellular elimination in wounds

While past studies have suggested some potential signals for the elimination of the various populations of cells in tissue repair, the mechanisms of how the cells disappear needs to be addressed. The cells involved in each phase disappear from a wound by one of three potential mechanisms: necrosis, emigration or apoptosis. Necrosis occurs in pathologic tissue repair but for most wounds, healing proceeds without excessive inflammation and resulting tissue damage. Necrosis clearly induces

Apoptosis signals in specific cell types involved in tissue repair

The first cell to arrive in the wound is the neutrophil. Neutrophils are essential in the defense against invading organisms. Their activity is also blamed for local and distant tissue damage through the release of oxygen free radicals and proteases. A predominant hypothesis for the pathophysiology of acute respiratory distress syndrome, for example, is through the activation of neutrophils in an extensive wound which then enter the systemic circulation and adhere to endothelial cells in the

Role of apoptosis in pathologic tissue repair

Many diseases involve dysregulated apoptosis. Cancer is the obvious process that involves a loss of normal apoptosis leading to uncontrolled cellular proliferation. Excessive apoptosis can also be pathologic in such illnesses as autoimmune diseases. A healing wound must also reach an equilibrium of proliferation and apoptosis to reach a steady state of a totally mature scar. During the inflammatory phase, decreased apoptotic activity may lead to an excessive and uncontrolled inflammatory

Summary

Apoptosis plays an essential role in the orchestration of the rapidly changing populations of cells that are involved in the healing of all tissues. For the vast majority of wounds, the controls of proliferation lead to an expeditious closure of a wound. Occasionally, the balance between increased and decreased cellular numbers loses its balance and leads to pathologic tissue repair. By understanding not only the cellular controls that promote proliferation but also decreasing cell numbers

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