Inflammation, cytokines, CRP, and MMPs: What is all this stuff?

April 1, 2010
Periodontal disease is a bacterial infection caused by a limited number of pathogens in the oral biofilm ...

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Periodontal disease is a bacterial infection caused by a limited number of pathogens in the oral biofilm, with tissue destruction resulting from the subsequent immuno-inflammatory response. Another way of stating this is, the etiology of periodontal disease is bacterial infection; the pathogenesis is inflammatory.

The immune system is extremely complex and loaded with a wide variety of factors, events, terms, and abbreviations including inflammatory mediators, cytokines, CRP, MMPs, IL-1, TNF-α, TLRs, neutrophils, and others. What is all this stuff, what does it do, and what does it have to do with dental care? In short, they are all inflammatory mediators released by the body in response to tissue damage or invasion by a pathogen.

The body initially responds to accumulating biofilm with a low level inflammatory response, manifesting as gingivitis. The primary physical properties of this early inflammatory response are blood vessel dilation and the development of gaps in the blood vessel walls, resulting in the delivery of blood and inflammatory mediators to the infected gingival tissues.

The net flow of blood out of the capillaries into the gingiva increases the volume in the gingival tissues, clinically resulting in the redness, swelling, and bleeding typically seen in gingivitis. The purpose of the body’s response is to prevent tissue damage, destroy the infective microbes, and activate repair processes necessary to restore health. These are very rapid processes that occur immediately after the onset of infection.

The whole process starts with the body recognizing the bacterial invasion of the gingival epithelial cells. Embedded in the cell membrane of the gingival epithelial cells (and many others including the skin and GI tract) are proteins called Toll-like receptors or TLRs.

They are transmembrane proteins that extend through the gingival epithelial cell membrane, having a portion outside the cell and a portion inside the cell. They are the body’s alarm system. They recognize the presence of the bacterial endotoxins. The TLRs then mobilize the inflammatory response.

Early in the process, activation of immune system cells occurs, starting with macrophages. Macrophages are involved in the destruction of bacteria and secretion of inflammatory mediators necessary to combat the infection.

Among the earliest inflammatory mediators secreted by the immune system cells are cytokines. Cytokines are small proteins that function as signaling compounds.

Examples of cytokines include the various interleukins (IL) such as IL-1, IL-6, IL-1β and TNF-α (tumor necrosis factor-alpha). Cytokines facilitate immune cell signaling resulting in the release of a variety of compounds necessary to the inflammatory response.

If the initial inflammatory response does not resolve the infection, chronic inflammation occurs. The chronic immuno-inflammatory response is what causes perio tissue destruction. During the immune system response, the liver releases C-reactive protein, or CRP. The C stands for “cross,” so CRP is a cross reactive protein.

CRP is released by the liver in response to injury, inflammation, or infection. It helps the body recognize foreign pathogens and the body’s own damaged cells and attracts other inflammatory mediators to a damaged or infected site. CRP also marks the perio pathogens for destruction by white blood cells. The primary white blood cells responsible for killing invading pathogens are neutrophils.

When periodontitis develops or progresses, hard- and soft-tissue destruction is primarily the result of degradation by enzymes, including collagenase. Collagen is a structural protein found in every area of the body, including the periodontium.

Since collagen fibers are made of proteins, the enzymes responsible for removing damaged, worn out, or traumatized collagen are protein-degrading enzymes called proteinases. There are many types of proteinases, including a group called matrix metalloproteinases or MMPs.

More than 30 MMPs have currently been identified. Several of these degrade collagen including MMP-1, MMP-8, and MMP-13, thereby being classified as collagenases. During chronic inflammation, these collagen-degrading MMPs break down the gingival soft tissue and play a part in bone resorption.

Knowledge of the inflammatory response and mediators is important since treatment modalities that address the inflammatory response will become a part of our armamentarium in the near future. It always comes back to the treatment we provide for our patients.

Dr. Richard Nagelberg has practiced general dentistry in suburban Philadelphia for more than 27 years. He is a speaker, advisory board member, consultant, and key opinion leader for several dental companies and organizations. He lectures extensively on many topics centered on understanding the impact dental professionals have beyond the oral cavity. Contact him at [email protected].

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