Persistence of inflammatory cytokines cause a spectrum of chronic progressive diseases: implications for therapy.
Chronic progressive disease (CPD) are the Western world's major cause of mortality (National Center for Health Statistics. Vol. 52. National vital 176 statistics reports. Deaths: final data for 2001; 2003, p. 3). Most chronic diseases present with symptoms and signs specific for the dysfunctional organ. Nonetheless, substantial commonalities are identifiable at the tissue and cellular level. These include a striking increase in inflammatory cytokines in both the tissue and the serum, accompanied by tissue destruction, apoptosis and tissue fibrosis. Individual inflammatory cytokines possess the capacity to induce these tissue effects in vitro and in vivo. Further, an elevation in systemic levels of cytokines and CRP predict an increase risk at all stages of these diseases. Therapies that inhibit the stimuli, the mediators or the responses to persistent inflammation appear to have an inhibitory effect on progression of specific diseases. We hypothesize that a unifying paradigm for CPD can be constructed based on these observations. Destabilizing stimuli activate the normal protective homeostatic inflammatory response in tissue. As the stimulus is eliminated and tissue heals, the inflammatory response recedes, re-establishing homeostasis. If inflammatory cytokines persist, however, both cell apoptosis and tissue fibrosis can be induced. Two aspects of evolution provide a potential mechanistic basis for this hypothesis. We may speculate that Darwinian selection favored early development of a system that channeled a broad spectrum of external and internal challenges through a generic response system. Thus, the mediators that respond to noxious stimuli became universal throughout organisms and species. Because these genetic responses were part of the DNA programming of all cells prior to differentiation, the tissue response to inflammation is also both uniform in nature, and narrow in scope. Subsequent cell differentiation resulted in vast differences in tissue function, so that organ dysfunction appears with the myriad symptoms and signs we recognize as individual diseases. Interference with inflammatory cytokines, e.g., with HMG Coa reductase inhibitors, inhibits a spectrum of chronic progressive diseases, independent of any LDL lowering effect.
Forrester
James S
JS
Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, United States. forrester@cshs.org
Bick-Forrester
Justin
J
D017209:Apoptosis; D005075:Biological Evolution; D002908:Chronic Disease / Q000628:therapy*; D016207:Cytokines / Q000096:biosynthesis*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018450:Disease Progression; D019143:Evolution, Molecular; D006801:Humans; D007249:Inflammation; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL / Q000737:chemistry; D008962:Models, Theoretical
D016207:Cytokines; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D004247:DNA