Molecular and cellular regulation of wound healing; what goes wrong when wounds fail to heal or heal too much?

Published on October 7, 2014   45 min
0:00
Hello, everyone. I'm Gregory Schultz, a biochemist at the University of Florida, and Professor of Obstetrics and Gynecology, and Director of the Institute for Wound Research. This presentation will deal with the basic molecular and cellular regulation of normal wound healing. But in addition, we'll look at what goes wrong when wounds fail to heal, or heal too much.
0:27
A brief overview of the topics that we will discuss today includes considering wound healing as a spectrum of outcomes, that is normal scars, but in addition fibrotic scars or chronic wounds. We will begin by reviewing the sequential phases of normal wound healing, and I especially want to emphasize the beneficial effects of controlled information and protease activities. Because I will contrast the beneficial effects of controlled information and protease activities with the detrimental effects on healing that occurs when chronic inflammation is caused by planktonic, and especially biofilm bacteria. And I'll show you that these lead to elevated levels of protease activities, especially the matrix metalloproteinase, or MMPs. Because these proteases destroy proteins that are essential for healing, such as the Extracellular Matrix, or ECM proteins, growth factors, or their receptors. And especially we'll also learn about the key roles that Transforming Growth Factor Beta or TGFB and CTGF, or Connective Tissue Growth Factor, play in stimulating excessive scar formation, or known clinically as fibrosis. And we'll look at some new ways to try to reduce pathological scar formation.
1:51
So let's begin by thinking of wound healing as a spectrum of clinical outcomes. In normal wound healing, we can see in this image of a good scar that has formed in an injury that's close to the hairline. And you can probably just barely see the slight indentation and slight abnormal appearance of the skin. But this is a very good cosmetic and functional outcome for a typical acute injury. At one end of the spectrum of wound healing however, is excessive healing or fibrosis. And here you can see an example of another acute incision that was made near the hairline of this person. But instead of forming a normal looking scar, this has formed a hypertrophic scar, which has excessive amounts of scar tissue and has both impaired functional, as well as visual appearance. At the low end or the infrared range of the spectrum of wound healing is the inadequate healing, or chronic wound healing. Shown here is an example of a venous leg ulcer. And so what we'll do in this presentation is look at normal healing, and then look at the causes and effects of excessive or inadequate healing from a molecular and cellular perspective.
3:09
Let's begin by just recognizing that normal acute wound healing in the skin occurs through four phases. These are hemostasis, inflammation, repair, and remodeling. We're going to deal with each of these phases in more detail in subsequent slides. But I just want to emphasize that obviously during the hemostasis phase of acute injury, this is when the clotting cascade activates. And the prothrombin gets activated to thrombin. It cleaves fibrinogen to fibrin, and a fibrin clot forms, and trapping the red blood cells. It basically prevents us from hemorrhaging to death. But also very important is that the formation of the fibrin clot stimulates platelets in the blood to degranulate. And as we'll see, the components within the platelet granules contain both growth factors as well as pro-inflammatory cytokines. And it's that local release of the platelet granules that really begins the inflammatory process by drawing in the inflammatory cells. And the wound then moves within about two to three days into the inflammatory phase, where neutrophils and macrophages come into the area of the injury. As we'll see, they do very important things of engulfing and killing bacteria, as well as releasing proteases that produce initial debridement. But in the absence of continued inflammatory stimulation, such as bacteria, the inflammatory phase undergoes a spontaneous regression so that it peaks at about five to seven days, and by about two weeks it's essentially back to levels seen in normal skin. That allows the wound then to move into the repair phase. This again, as we look at, includes multiple processes of converting the provisional fibrin matrix into an initial scar matrix that allows new blood vessels or angiogenesis to occur. It allows myofibroblasts to contract the wound. And it also allows epithelial cells to begin moving across the initial collagen scar matrix. And so by about two to three weeks, most injuries in the skin have epithelialized. And we think, well the wound is healed. But as you know, actually the wound undergoes a significant amount of remodeling for the next six to nine months, in which that initial irregular scar matrix is slowly removed by the control actions proteases, allowing the initial irregular scar matrix to remodel back to a more normal durable matrix. But particularly for us today, we want to look at two of these phases. And I'll show you that chronic inflammation is a major cause for the prolonged elevation of protease activities in wounds, which prevents the wounds from moving out of the inflammatory phase, into the repair phase. And I'll also show you that the repair phase, when it is extended for a long period of time at high levels, actually is what causes the excessive scar formation or fibrosis. So again, we'll look at the normal process of healing. And then focus in on the inflammatory and repair phases, and how they play roles in chronic wound healing or fibrosis.
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Molecular and cellular regulation of wound healing; what goes wrong when wounds fail to heal or heal too much?

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