The Inflammatory Process
The Acute Inflammatory Response
Inflammation, the adaptive immune response to tissue injury or infection, plays a central role in metabolism in a variety of organisms.11
At its most basic level, an acute inflammatory response is triggered by 1) tissue injury (trauma, exposure to heat or chemicals); or 2) infection by viruses, bacteria, parasites, or fungi. The classic manifestation of acute inflammation is characterized by four cardinal signs: Redness and heat result from the increased blood flow to the site of injury. Swelling results from the accumulation of fluid at the injury site, a consequence of the increased blood flow. Finally, swelling can compress nerve endings near the injury, causing the characteristic pain associated with inflammation. Pain is also important to make the organism aware of the tissue damage. Additionally, inflammation in a joint usually results in a fifth sign (impairment of function), which has the effect of limiting movement and forcing rest of the injured joint to aid in healing.
A well-controlled acute inflammatory response has several protective roles:
- It prevents the spread of infectious agents and damage to nearby tissues;
- helps to remove damaged tissue and pathogens; and
- assists the body's repair processes
However, a third type of stimuli, cellular stress and malfunction, triggers chronic inflammation, which, rather than benefiting health, contributes to disease and age-related deterioration via numerous mechanisms.
Cellular Stress and Chronic, Low-Level Inflammation
Mitochondria—cellular organelles responsible for generating biochemical energy in the form of adenosine triphosphate (ATP)—are a fundamentally necessary component of life in higher organisms. In fact, in the case of sophisticated multicellular life forms, organismal viability depends upon optimal mitochondrial function. Paradoxically, mitochondrial processes can also bring about a tissue-destroying inflammatory mediator known as the inflammasome; this phenomenon is provoked by damaged and dysfunctional mitochondria.12
Mitochondrial dysfunction arises consequent of exposure to exogenous (eg, environmental toxins, tobacco smoke) and endogenous (eg, reactive oxygen species) stressors, and as a result of the aging process itself. For example, a byproduct of mitochondrial energy generation is the creation of free radical molecules. Free radicals can damage cellular structures and initiate a cascade of proinflammatory genetic signals that ultimately results in cell death (apoptosis), or worse, uncontrolled cell growth—the hallmark of cancer.
Aging is associated with declining mitochondrial efficiency and increased production of free radical molecules. Recent research identifies this age-associated aberration of mitochondrial function as a principle actuator of chronic inflammation.13 Specifically, mitochondrial dysfunction brings about inflammation as follows:
- Accumulation of free radicals induces mitochondrial membrane permeability;
- Molecular components normally contained within the mitochondria leak into the cytoplasm (intracellular fluid in which cellular organelles are suspended);
- Cytoplasmic pattern recognition receptors (PRR's), which detect and initiate an immune response against intracellular pathogens, recognize the leaked mitochondrial molecules as potential threats;
- Upon detection of the potential threat, PRR's form a complex called the inflammasome that activates the inflammatory cytokine interleukin-1β, which then recruits components of the immune system to destroy the “infected” cell.14
These four steps represent a simplified scheme of mitochondrial dysfunction leading to cellular destruction; however, intracellular free radicals are not the only inducers of inflammatory cell death.
Circulating sugars, primarily glucose and fructose, are culprits as well. When these “blood sugars” come in contact with proteins and lipids a damaging reaction occurs forming compounds called advanced glycation end products (AGEs). AGEs bind to the cell-surface receptor called receptor for advanced glycation end products, or RAGE. Upon activation, RAGE triggers the movement of the inflammatory mediator nuclear factor kappa-B (NF-κB) to the nucleus, where it activates numerous inflammatory genes.15 AGEs are primarily formed in vivo, and glycation is exacerbated by elevated blood sugar levels. However, dietary AGEs also contribute to inflammation; they are abundant in foods cooked at high temperatures, especially red meat.16,17
Additional biochemical inducers of a chronic inflammatory response include:
- Uric acid (urate) crystals, which can be deposited in joints during gouty arthritis; elevated levels are a risk factor for kidney disease, hypertension, and metabolic syndrome18,19;
- Oxidized lipoproteins (such as LDL), a significant contributor to atherosclerotic plaques20; and
- Homocysteine, a non-protein-forming amino acid that is a marker and risk factor for cardiovascular disease, and may increase bone fracture risk.21
Together, these proinflammatory instigators promote a perpetual low-level chronic inflammatory state called para-inflammation.11
Although it progresses silently, para-inflammation presents a major threat to the health and longevity of all aging humans. Chronic, low-level inflammation is associated with common diseases including cancer, type II diabetes, osteoporosis, cardiovascular diseases, and others. Thus, by targeting the myriad physiological variables that can inaugurate an inflammatory response, one can effectively temper chronic inflammation and reduce their risk for inflammatory diseases.