Inflammatory pathway in atherosclerosis biological basis of biomarkers in prediction and prognostication in atherosclerotic disease

Recognition of the role of inflammation as a master regulator of atherogenesis has provided a fresh intellectual construct for understanding this disease. This new scientific foundation for understanding atherogenis also furnishes insights into novel therapeutic targets that may assist its mitigation. While inflammation biology currently furnishes new insights into the mechanism of benefit of existing therapeutics, the promise of targeted anti-inflammatory interventions to prevent or treat atherosclerosis will require much greater time and effort. Yet, one type of practical application of inflammation biology promises favorable outcome in terms of more prompt clinical applicability. Biomarkers of inflammation may soon merit inclusion in clinical application, the topic of many contributions to this volume.

As data concerning the utility ofbiomarkers of inflammation in prospective cardiovascular risk prediction emerged, they appeared to fit into a pattern. One theoretical construct may help to systematize the biological basis ofbiomarkers ofinflammation in the cardiovascular arena (Fig. 4) (30). According to this hypothesis, a first wave ofprimary proinflammatory cytokines could arise from either vascular or extravascular sources (Fig. 4, top). Examples of primary proinflammatory cytokines include the soluble mediators IL-ip and tumor necrosis factor (TNF)-a. Intravascular sources could include the atheroma itself, a hotbed of inflammatory signaling, as already discussed. Extravascular sources could include foci of chronic infection, such as prostatitis, bronchitis, periodontal disease, or stasis or ischemic ulcers. Unfortunately, another potential source of extravascular inflammatory stimuli, visceral adipose tissue, will become more prominent owing to the currently increasing prevalence of obesity.

The inflammatory stimuli produced by primary proinflammatory cytokines may undergo amplification through the induction of IL-6 production. Multiple cell types including vascular SMCs and ECs can produce large amounts of IL-6 when exposed to IL-ip or TNF-a (31-34). This amplification magnifies the inflammatory output owing to the initial proinflammatory cytokine signals.

IL-6, a soluble mediator, controls the hepatic acute-phase response. This coordinated change in the program of liver protein synthesis typifies the organism's response to injury or inflammation. When exposed to IL-6, hepatocytes augment their expression of proteins ofthe acute-phase response, including fibrinogen; PAI-1; serum amyloid A (SAA); and, notably, C-reactive protein (CRP) (see Chapters 16 and 17). The primary proinflammatory cytokines can also impinge on vascular endothelial and other cells to augment their expression of leukocyte adhesion molecules, as mentioned previously. Many cell-surface molecules including certain leukocyte adhesion molecules can undergo proteolytic cleavage and enter the circulation in a shed form (Fig. 4, middle). Both acute-phase reactants from the liver and shed adhesion molecules enter peripheral blood accessible to sampling by routine venipuncture (Fig. 4, bottom) (see Chapter 18).

The scheme depicted in Fig. 4 provides a framework for understanding the biological basis of biomarkers of inflammation in cardiovascular and other diseases. Of course,

Sources Soluble Biomarkers

Fig. 4. A proposed inflammatory pathway that operates during atherogenesis can augment inflammatory biomarker concentrations in peripheral blood. See text for explanation. sCD40L, soluble CD40L; IL, interleukin; TNF, tumor necrosis factor; sVCAM, soluble vascular adhesion molecule;PAI, plasminogen activator inhibitor; SAA, serum amyloid A; ICAM-1, intercellular adhesion molecule-1.

Fig. 4. A proposed inflammatory pathway that operates during atherogenesis can augment inflammatory biomarker concentrations in peripheral blood. See text for explanation. sCD40L, soluble CD40L; IL, interleukin; TNF, tumor necrosis factor; sVCAM, soluble vascular adhesion molecule;PAI, plasminogen activator inhibitor; SAA, serum amyloid A; ICAM-1, intercellular adhesion molecule-1.

evidence is lacking for the sequence of events as depicted and described. Nevertheless, this model provides a useful working hypothesis to provide some order in the burgeoning roster of biomarkers described on an ongoing basis in contemporary literature. Clearly other contributors to peripherally sampled biomarkers exist. Notably, activated platelets can shed CD40L (see Chapter 18) and likely furnish the bulk of this inflammatory biomarker in circumstances such as ACS (35). Additionally, sources of acute-phase reactants other than the liver may contribute to their appearance in peripheral blood. In particular, evidence has appeared for CRP production locally within atherosclerotic lesions. However, given the size of the liver compared to the mass of atherosclerotic plaques, on a quantitative basis, the liver likely contributes the greatest share of CRP and other acute-phase reactants sampled in venous blood. The strategic location of visceral adipose tissue, draining into the portal circulation and perfusing the liver, provides another basis for hypothesizing a principal role for hepatocytes as a source of acute-phase reactants.

Because it incorporates the notion of an amplification loop, the model presented in Fig. 4 also helps researchers understand the utility of inflammatory biomarkers. Just a few molecules of a primary proinflammatory cytokine can beget the production of many more molecules of IL-6, the major mediator ofthe acute-phase response. This amplification loop helps in the understanding of how relatively small volumes of inflamed atherosclerotic plaques may nonetheless generate substantial signal measurable in peripheral blood, even in apparently healthy individuals.

Was this article helpful?

0 0
The Mediterranean Diet Meltdown

The Mediterranean Diet Meltdown

Looking To Lose Weight But Not Starve Yourself? Revealed! The Secret To Long Life And Good Health Is In The Foods We Eat. Download today To Discover The Reason Why The Mediterranean Diet Will Help You Have Great Health, Enjoy Life And Live Longer.

Get My Free Ebook


Post a comment