We started our last blog (#14) on chronic inflammation (CI) by mentioning its distinguishing characteristics (versus acute inflammation) including its pathogenic etiologies; then its immunologic, and molecular level; then its pharmacology and pharmacodynamics; and finally its clinical and immunotherapeutic considerations. We covered only the pathogenic and immunologic etiologies, so we have more work to do. Let’s try to get through CI’s pharmacology and pharmacodynamics in this blog and then finish up with the clinical and immunotherapeutic considerations of CI in Blog #15.
The pharmacology of CI (cytokines, chemotactic factors, enzymes, hormones, proteoglycans,, and reactive molecules) of the inflammatory cascade are controlled by complex neurogenic and nonneurogenic mechanisms which we will be discussing in Blog #17. The immunochemical responses (pharmacodynamics) that drive the immune response and CI represents only a portion of the elements involved. Proinflammatory mediators and immunomodulators (amplifications, supplementation, suppression) of these chemical and molecular components elicit therapeutic effects we’ll discuss in a moment. The immune cells discussed in earlier blogs (macrophages, monocytes, etc.) release cytokines such as IL-1, 3, and 4 as well as a specialized cytokine, tumor necrosis factor (TNF-a) responsible for a wide range of signaling events within cells that lead to necrosis or apoptosis. Whereas this TNF-a protein is a potent proinflammatory cytokine, paradoxically it also has been identified as having an important role in the resistance of infection and cancers. As such, numerous biologics (complex drugs from living sources that target specific parts of the immune system to treat disease) are directed at TNF inhibition to allow for alternate drug selections in an effort to maximize inflammatory inhibition while minimizing suppression of TNF’s anti-infectious, anticancer properties. We’ll discuss this more in immunotherapies for CI as well as the upcoming blogs on immunotherapeutics, autoimmune diseases, cancers and infectious diseases. Through this comment, you can begin to see the implications of CI as the basis of all diseases – so too is its treatment).
Allow me to dive just a little deeper for a moment into the pharmacodynamics of CI for some more robust, albeit complex, but worthwhile information. Those circulating leukocytes (WBCs) that escaped from the blood vessels (diapedesis and extravasation) migrate to the disease site(s) and are activated by various cytokines and chemokines secreted by the macrophages and APCs. On activation, the leukocytes release additional cytokines and mediators of inflammation. The WBC neutrophils are also helping to destroy the antigen by phagocytosis through the release of reactive oxygen species. Cytokines such as IL-1, IL-6, TNF-a, and T- and B-lymphocytes are also an additional line of defense mediating inflammation through several complex mechanisms including secretion of cytokines and production of antibodies and immune complexes (remember Type III hypersensitivity reaction from Blog #5?). Circulating platelets also play a role in this pharmacodynamic process by platelet aggregation (adhering to the vessel wall forming thrombus) and mast cell degranulation releasing chemokines and inflammatory mediators (classic IgE allergic response in Type I hypersensitivity). Quite a demonstration of biochemistry and, in fact, the basis for our in-depth immunotherapy upcoming in Blog #21. What was the old DuPont saying? “Better living through chemistry.” Oops! I’m giving away my age?
Discussion Questions:
Among the array of cytokines associated with the inflammatory cascade, which produces the widest range of signaling events, and what is the unique characteristic of this cytokine?
During the extravasation of cytokines, chemokines, and immune cells from the blood vessels, which one, in particular, is most effective against an antigen, and by what process does it use?
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