Inflammation is the body’s natural response to infection or injury. It is characterized by redness, swelling, heat, and pain. This is caused by the immune system releasing chemicals that dilate blood vessels and bring more blood to the affected area. Inflammation is an important part of the healing process. However, if inflammation persists and becomes chronic, it can lead to serious health problems.
What is inflammation?
Inflammation occurs when the immune system identifies harmful stimuli like pathogens, damaged cells, irritants, or toxins. It responds by releasing chemical mediators that cause blood vessels to leak fluid into tissues. This leads to swelling that physically blocks invading pathogens and isolates the injured tissue. Inflamed areas experience increased blood flow which results in redness and heat. The swelling leads to pressure on nerve endings which causes pain.
Inflammation is driven by a variety of immune cells. Mast cells release histamine which dilates blood vessels. Basophils release inflammatory mediators like leukotrienes. Eosinophils secrete proteins toxic to parasites. Neutrophils, monocytes, and macrophages release cytokines, chemokines, and proteases that amplify the inflammatory response.
Acute inflammation normally lasts for a few days. It is self-limiting and resolves with the removal of harmful stimuli. The inflammatory process stimulates tissue repair and regeneration. However, if acute inflammation fails to eliminate the offender, it can lead to chronic inflammation which underlies many diseases.
What happens in chronic inflammation?
Chronic inflammation persists over months and years. It is characterized by simultaneous destruction and healing of tissues. This simultaneous injury and repair results in remodeling of tissue architecture and function.
Chronic inflammatory responses are driven by macrophages and lymphocytes. These cells sustain inflammation by producing inflammatory mediators like interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF). High levels of these molecules cause tissue damage.
Chronic inflammation causes blood vessels to become leaky. This allows inflammatory cells and proteins to enter tissues leading to redness, swelling, heat, pain, and loss of function. The swollen inflamed area is infiltrated by immune cells like macrophages, lymphocytes, and plasma cells.
Inflammatory cells also release reactive oxygen species (ROS) and hydrolytic enzymes that damage cells and tissues. Matrix metalloproteinases break down the extracellular matrix causing loss of tissue structure and function.
Unresolved inflammation stimulates fibrosis. This is excessive deposition of extracellular matrix components like collagen. Fibrosis causes scarring and thickening of tissue which impairs normal function.
The cytokines and chemokines released during chronic inflammation also stimulate angiogenesis. This results in growth of new blood vessels that sustain the supply of inflammatory cells.
Diseases caused by chronic inflammation
Chronic inflammation is now believed to be the root cause of many diseases. Some examples include:
Rheumatoid arthritis
In rheumatoid arthritis, chronic inflammation of the joints causes painful swelling, joint damage, and disability. It is caused by inflammatory cytokines and autoantibodies produced by immune cells.
Inflammatory bowel disease
Inflammatory bowel disease involves chronic inflammation of the gastrointestinal tract. It includes Crohn’s disease and ulcerative colitis which cause abdominal pain, diarrhea, and intestinal damage.
Asthma
Asthma occurs due to chronic inflammation of the airways. This causes wheezing, breathlessness, chest tightness, and coughing.
Psoriasis
Psoriasis causes red, scaly patches on the skin. It is driven by chronic inflammation mediated by T cells and inflammatory cytokines.
Atherosclerosis
Atherosclerosis involves chronic inflammation of the arterial blood vessels. This drives plaque formation and narrowing of arteries which can lead to heart attacks and strokes.
Obesity
Obesity has been characterized as a state of chronic low-grade inflammation. Expanding adipose tissue releases inflammatory molecules which impair metabolic function.
Diabetes
Chronic inflammation contributes to insulin resistance which underlies type 2 diabetes. Inflammatory mediators block insulin signaling pathways.
Neurodegenerative diseases
Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) involve chronic neuroinflammation which drives neural damage and death.
Mechanisms of chronic inflammation
There are several key reasons why acute inflammation transitions into chronic inflammation:
Failure to eliminate pathogen
Chronic infections persist when the body cannot clear the pathogen. Persistent pathogens like hepatitis C virus, HIV, and Helicobacter pylori cause ongoing infection-induced inflammation.
Autoimmunity
Loss of immunological tolerance leads to autoimmunity where the immune system attacks the body’s own tissues. Autoimmune diseases like rheumatoid arthritis involve chronic inflammation driven by autoantibodies and autoreactive T cells.
Irritants
Irritants like industrial pollutants, smoke, and allergens trigger recurrent bouts of acute inflammation which lead to tissue damage and chronic inflammation.
Obesity
Obesity causes adipose tissue to release inflammatory mediators like TNF-alpha, IL-6, and monocyte chemoattractant protein-1 (MCP-1). Additionally, obese adipose tissue is infiltrated by pro-inflammatory macrophages.
Tissue injury and cell death
Repeated tissue insults, cell death, and necrosis release molecules called damage-associated molecular patterns (DAMPs). These DAMPs activate innate immune receptors called pattern recognition receptors (PRRs) which propagate inflammation.
Genetic factors
Gene variants linked to excessive inflammatory responses are risk factors for chronic inflammatory disorders. Genetic differences in cytokine receptors, signalling proteins, and PRRs can drive uncontrolled inflammation.
Aging
Aging is associated with increased blood levels of pro-inflammatory cytokines like IL-6 and TNF-alpha which contributes to low-grade chronic inflammation in older individuals. Cellular senescence also drives age-related chronic inflammation.
Consequences of chronic inflammation
Chronic inflammation can have devastating effects throughout the body:
Tissue damage and loss of function
As mentioned earlier, inflammatory cells and molecules damage tissue architecture leading to loss of function. For example, inflammation damages the joint cartilage and bone in rheumatoid arthritis.
Pain
Mediators like bradykinin, prostaglandins, and nerve growth factor released during inflammation activate pain sensing neurons. This causes chronic inflammatory pain.
Fatigue
Inflammatory cytokines promote symptoms of sickness like loss of appetite and chronic fatigue.
Cancer
Chronic inflammation often precedes and accelerates cancer development. Inflammatory cells, chemokines, cytokines, and ROS create a tumor-promoting microenvironment.
Depression and anxiety
Pro-inflammatory cytokines communicate with the brain and contribute to the pathogenesis of anxiety and depression.
Growth retardation
Children with chronic inflammatory diseases often experience growth retardation and delayed puberty. Inflammatory cytokines suppress the growth hormone-IGF-1 axis to slow growth.
Muscle wasting
Elevated TNF-alpha levels cause cachexia characterized by loss of muscle and fat mass. This is mediated by the stimulation of ubiquitin-proteasome pathways that degrade muscle proteins.
Insulin resistance
Inflammatory signaling impairs insulin receptor function leading to reduced glucose uptake and utilization. This inflammatory etiology underlies type 2 diabetes.
Premature aging
Chronic inflammation is proposed to be a key driver of accelerated biological aging. “Inflammaging” erodes cellular and tissue function leading to the early onset of age-related diseases.
How to resolve chronic inflammation
Chronic inflammation often requires urgent treatment to prevent tissue damage and disease progression. Anti-inflammatory strategies include:
Lifestyle changes
Eating a healthy diet, exercising regularly, avoiding smoking, and reducing stress can help resolve chronic inflammation. Obesity and inactivity promote inflammation so weight loss and increased activity are beneficial.
Medications
Non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen help alleviate inflammatory symptoms but can have gastrointestinal and cardiovascular side effects with long-term use. Corticosteroids and newer biologic drugs that block inflammatory cytokines are also used to treat chronic inflammatory disorders.
Natural compounds
Some natural compounds like curcumin, omega-3 fatty acids, green tea, and resveratrol have anti-inflammatory effects. However, clinical evidence for their efficacy is limited.
Probiotics and prebiotics
Altering the gut microbiome composition with probiotics and prebiotics helps reduce inflammation originating from the gastrointestinal tract.
Surgery
Removing infected or damaged tissues surgically is necessary in some cases to stop chronic inflammation.
Conclusion
Chronic inflammation is a major driver of disease and disability worldwide. It is characterized by inflammatory cell infiltration and elevated cytokine levels that cause simultaneous tissue damage and repair. This ultimately remodels tissue architecture in a pathological manner. Chronic inflammation is now believed to underlie obesity, type 2 diabetes, atherosclerosis, autoimmunity, neurodegeneration, and even aging itself. Thus, identifying ways to resolve unremitting inflammation is crucial for preventing and treating many chronic diseases. Lifestyle changes, anti-inflammatory medications, probiotics, natural compounds, and surgery are some strategies to dampen inflammation before it causes irreversible harm.