Inflammation is a biological response of the immune system that can be triggered by a variety of factors, including pathogens, damaged cells and toxic compounds.
These factors may induce acute and/or chronic inflammatory responses in the heart, pancreas, liver, kidney, lung, brain, intestinal tract and reproductive system, potentially leading to tissue damage or disease.
Both infectious and non-infectious agents and cell damage activate inflammatory cells and trigger inflammatory signaling pathways, most commonly the NF-κB, MAPK, and JAK-STAT pathways.
Inflammation is the immune system’s response to harmful stimuli, such as pathogens, damaged cells, toxic compounds, or irradiation , and acts by removing injurious stimuli and initiating the healing process.
Inflammation is therefore a defense mechanism that is vital to health.
Usually, during acute inflammatory responses, cellular and molecular events and interactions efficiently minimize impending injury or infection.
This mitigation process contributes to restoration of tissue homeostasis and resolution of the acute inflammation.
However, uncontrolled acute inflammation may become chronic, contributing to a variety of chronic inflammatory diseases.
At the tissue level, inflammation is characterized by redness, swelling, heat, pain, and loss of tissue function, which result from local immune, vascular and inflammatory cell responses to infection or injury.
Important microcirculatory events that occur during the inflammatory process include vascular permeability changes, leukocyte recruitment and accumulation, and inflammatory mediator release.
Various pathogenic factors, such as infection, tissue injury, or cardiac infarction, can induce inflammation by causing tissue damage.
The etiologies of inflammation can be infectious or non-infectious (Table (Table1).
Table 1
| Non-infectious factors | Infectious factors |
|---|---|
| Physical: burn, frostbite, physical injury, foreign bodies, trauma, lionizing radiation Chemical: glucose, fatty acids, toxins, alcohol, chemical irritants (including fluoride, nickel and other trace elements) Biological: damaged cells Psychological: excitement |
Bacteria viruses other microorganisms |
In response to tissue injury, the body initiates a chemical signaling cascade that stimulates responses aimed at healing affected tissues.
These signals activate leukocyte chemotaxis from the general circulation to sites of damage.
These activated leukocytes produce cytokines that induce inflammatory responses .
Without inflammation as a physiological response, wounds would fester, and infections could become deadly.
However, if the inflammatory process goes on for too long or if the inflammatory response occurs in places where it is not needed, it can become problematic.
Chronic inflammation has been linked to certain diseases such as heart disease or stroke, and may also lead to autoimmune disorders, such as rheumatoid arthritis and lupus. But a healthy diet and lifestyle can help keep inflammation under control.
Acute inflammation
Acute inflammation occurs after a cut on the knee, a sprained ankle or a sore throat. It’s a short-term response with localized effects, meaning it works at the precise place where a problem exists.
The telltale signs of acute inflammation include redness, swelling, heat and sometimes pain and loss of function, according to the National Library of Medicine.
In the case of acute inflammation, blood vessels dilate, blood flow increases and white blood cells swarm the injured area to promote healing, said Dr. Scott Walker, a family practice physician at Gunnison Valley Hospital in Utah.
This response is what causes the injured area to turn red and become swollen.
During acute inflammation, chemicals known as cytokines are released by the damaged tissue.
The cytokines act as “emergency signals” that bring in your body’s immune cells, hormones and nutrients to fix the problem, Walker said.
In addition, hormone-like substances known as prostaglandins create blood clots to heal damaged tissue, and they also trigger pain and fever as part of the healing process.
As the body heals, the acute inflammation gradually subsides.
Inflammatory cytokines
Cytokines (Table (Table2)2) are predominantly released from immune cells, including monocytes, macrophages, and lymphocytes. Pro- and anti-inflammatory cytokines facilitate and inhibit inflammation, respectively.
Inflammatory cytokines are classified as ILs, colony stimulating factors (CSF), IFNs, TNFs, TGFs, and chemokines, and are produced by cells primarily to recruit leukocytes to the site of infection or injury [58].
Cytokines modulate the immune response to infection or inflammation and regulate inflammation itself via a complex network of interactions.
However, excessive inflammatory cytokine production can lead to tissue damage, hemodynamic changes, organ failure, and ultimately death [59, 60].
A better understanding of how to regulate cytokine pathways would allow for more accurate identification of agent-mediated inflammation and the treatment of inflammatory diseases [58].
Table 2
| Cytokine | Family | Main sources | Function |
|---|---|---|---|
| IL-1β | IL-1 | Macrophages, monocytes | Pro-inflammation, proliferation, apoptosis, differentiation |
| IL-4 | IL-4 | Th-cells | Anti-inflammation, T-cell and B-cell proliferation, B-cell differentiation |
| IL-6 | IL-6 | Macrophages, T-cells, adipocyte | Pro-inflammation, differentiation, cytokine production |
| IL-8 | CXC | Macrophages, epithelial cells, endothelial cells | Pro-inflammation, chemotaxis, angiogenesis |
| IL-10 | IL-10 | Monocytes, T-cells, B-cells | Anti-inflammation, inhibition of the pro-inflammatory cytokines |
| IL-12 | IL-12 | Dendritic cells, macrophages, neutrophils | Pro-inflammation, cell differentiation, activates NK cell |
| IL-11 | IL-6 | Fibroblasts, neurons, epithelial cells | Anti-inflammation, differentiation, induces acute phase protein |
| TNF-α | TNF | Macrophages, NK cells, CD4+lymphocytes, adipocyte | Pro-inflammation, cytokine production, cell proliferation, apoptosis, anti-infection |
| IFN-γ | INF | T-cells, NK cells, NKT cells | Pro-inflammation, innate, adaptive immunity anti-viral |
| GM-CSF | IL-4 | T-cells, macrophages, fibroblasts | Pro-inflammation, macrophage activation, increase neutrophil and monocyte function |
| TGF-β | TGF | Macrophages, T cells | Anti-inflammation, inhibition of pro-inflammatory cytokine production |
Inflammatory proteins and enzymes
Inflammatory proteins in the blood, including C-reactive protein (CRP), haptoglobin, serum amyloid A, fibrinogen, and alpha 1-acid glycoprotein [61], help restore homeostasis and reduce microbial growth independently of antibodies during trauma, stress, or infection [62].
Abnormal activation of certain enzymes, including high-mobility group box 1 (HMGB1), superoxide dismutase (SOD), glutathione peroxidase (GPx), NADPH oxidase (NOX), inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, play key roles in the development of inflammation-related diseases, such as cardiovascular disease and cancer [63–66].
For example, extracellular HMGB1 effects may be mediated by activation of TLR-coupled signaling pathways [67].
The primary target of extracellular HMGB1 is TLR4 [68], which triggers MyD88-dependent intracellular signaling cascades involved in activation of the NF-κB and MAPK pathways.
This leads to release of such inflammatory cytokines as TNF-α and IL-1β [67].
Inflammatory proteins and enzymes have been used as inflammation, infection, and trauma biomarkers in medicine.
Other inflammatory markers
Antioxidant defense systems, including antioxidant enzymes, influence oxidative stress. Elevated oxidative stress can induce production of reactive oxygen species (ROS), malondialdehyde (MDA), 8-Hydroxy-2-deoxyguanosine (8-OHdG) and isoprostanes [64, 69], each of which can activate various transcription factors, including NF-κB, AP-1, p53, and STAT.
Thus, this cascade can increase expression of genes encoding growth factors, inflammatory cytokines, and chemokines [70].
Oxidative stress is associated with the pathogenesis of multiple diseases, such as cardiovascular disease, cancer, diabetes, hypertension, aging, and atherosclerosis. Therefore, oxidative stress products can also be used as markers of the inflammatory response.
Cell types in inflammatory responses
The inflammatory response involves a highly coordinated network of many cell types. Activated macrophages, monocytes, and other cells mediate local responses to tissue damage and infection.
At sites of tissue injury, damaged epithelial and endothelial cells release factors that trigger the inflammatory cascade, along with chemokines and growth factors, which attract neutrophils and monocytes.
The first cells attracted to a site of injury are neutrophils, followed by monocytes, lymphocytes (natural killer cells [NK cells], T cells, and B cells), and mast cells [71–73].
Monocytes can differentiate into macrophages and dendritic cells and are recruited via chemotaxis into damaged tissues.
Inflammation-mediated immune cell alterations are associated with many diseases, including asthma, cancer, chronic inflammatory diseases, atherosclerosis, diabetes, and autoimmune and degenerative diseases.
Neutrophils, which target microorganisms in the body, can also damage host cells and tissues [74].
Neutrophils are key mediators of the inflammatory response, and program antigen presenting cells to activate T cells and release localized factors to attract monocytes and dendritic cells [7].
Macrophages are important components of the mononuclear phagocyte system, and are critical in inflammation initiation, maintenance, and resolution [75].
During inflammation, macrophages present antigens, undergo phagocytosis, and modulate the immune response by producing cytokines and growth factors.
Mast cells, which reside in connective tissue matrices and on epithelial surfaces, are effector cells that initiate inflammatory responses.
Activated mast cell release a variety of inflammatory mediators, including cytokines, chemokines, histamine, proteases, prostaglandins, leukotrienes, and serglycin proteoglycans [76].
Multiple groups have demonstrated that platelets impact inflammatory processes, from atherosclerosis to infection.
Platelet interactions with inflammatory cells may mediate pro-inflammatory outcomes.
The acute phase response (APR) is the earliest response to infection or injury, and some studies have indicated that platelets induce the APR [77].
After being recruited by inflammatory stimuli, immune cells amplify and sustain the APR by releasing local inflammatory mediators at the site of recruitment.
Chronic inflammation
Unlike acute inflammation, chronic inflammation can have long-term and whole-body effects.
Chronic inflammation is also called persistent, low-grade inflammation because it produces a steady, low-level of inflammation throughout the body, as judged by a small rise in immune system markers found in blood or tissue.
This type of systemic inflammation can contribute to the development of disease, according to a summary in the Johns Hopkins Health Review.
Low levels of inflammation can be triggered by a perceived internal threat, even when there isn’t a disease to fight or an injury to heal, andsometimes this signals the immune system to respond.
As a result, white blood cells swarm but have nothing to do and nowhere to go, and they may eventually start attacking internal organs or other healthy tissues and cells, Walker said.
Researchers are still working to understand the implications of chronic inflammation on the body and the mechanisms involved in the process, but it’s known to play a role in the development of many diseases.
For example, chronic inflammation has been linked to heart disease and stroke. One theory suggests that when inflammatory cells stay too long in blood vessels, they promote the buildup of plaque.
The body perceives this plaque as a foreign substance that doesn’t belong, so it tries to wall off the plaque from the blood flowing inside the arteries, according to the American Heart Association(AHA).
If the plaque becomes unstable and ruptures, it forms a clot that blocks blood flow to the heart or brain, triggering a heart attack or stroke.
Cancer is another disease linked with chronic inflammation. Over time, chronic inflammation can cause DNA damage and lead to some forms of cancer, according to the National Cancer Institute.
Chronic, low-grade inflammation often does not have symptoms, but doctors can test for C-reactive protein (CRP), a marker for inflammation in the blood.
High levels of CRP have been linked with an increased risk of heart disease. CRP levels can also indicate an infection, or a chronic inflammatory disease, such as rheumatoid arthritis or lupus, according to the Mayo Clinic.
Besides looking for clues in the blood, a person’s diet, lifestyle habits and environmental exposures can contribute to chronic inflammation. It’s important to maintain a healthy lifestyle to keep inflammation in check.
Anti-inflammatory diet
Anti-inflammatory diets have become popular in recent years.
The recommended foods are typical of a Mediterranean diet and include eating more fish, fresh fruits and vegetables, and healthy fats; eating moderate amounts of nuts; eating very little red meat; and drinking red wine in moderation.
Like the Mediterranean diet, the principles of an anti-inflammatory diet are healthful ones and the approach is nutritionally sound, according to the Mayo Clinic.
“Anti-inflammatory food components, such as omega-3 fats, protect the body against the possible damage caused by inflammation,” said Ximena Jimenez, a Miami-based nutritionist and spokesperson for the Academy of Nutrition and Dietetics.
An anti-inflammatory diet also means staying away from foods that can promote inflammation. It’s best to minimize the amount of foods you eat that are high in saturated and trans fats, such as red meats, dairy products and foods containing partially hydrogenated oils, according to the University of Wisconsin.
In addition, limit sugary foods and refined carbohydrates, such as white rice and bread. And cut back on the use of cooking oils and margarines that are high in omega-6 fatty acids, such as corn, safflower and sunflower oils.
Anti-inflammatory drugs and supplements
Currently, there are no prescription drugs that specifically target chronic inflammation, according to an article published in the Johns Hopkins Health Review.
However, there are plenty of over-the-counter and some prescription medications to treat acute, short-term inflammation.
The most common ones are the over-the-counter medications known as non-steroidal anti-inflammatory drugs (NSAIDs). They include aspirin, naproxen (Aleve) and ibuprofen (Advil and Motrin).
NSAIDs work by blocking the enzyme cyclooxygenase, which produces prostaglandins, a hormone-like substance that promotes inflammation, according to MedicineNet.
When over-the-counter medicines aren’t effective at relieving short-term pain and inflammation, there are also prescription-strength NSAIDs.
Acetaminophen (Tylenol) is another common pain reliever, but it does not relieve inflammation, according to the National Library of Medicine.
Corticosteroids, such as cortisone and prednisone, may be prescribed for inflammatory conditions, such as asthma and arthritis.
They may help suppress inflammation, but these powerful drugs also carry a risk of side effects, such as weight gain and fluid retention, according to the Mayo Clinic.
Several dietary supplements are said to have anti-inflammatory properties, such as devil’s claw, turmeric and willow bark.
Although there is some limited evidence that a few natural products may provide modest benefits for acute inflammation, in general, there is insufficient evidence to support the use of many of these products for inflammatory conditions, according to the National Center for Complimentary and Integrative Health.
