The past two decades could easily be considered the golden age of recognizing the importance of inflammation in medicine. Research has pointed to the presence of inflammation in some of the most serious human illnesses, including cardiovascular disease, diabetes, cancer, Alzheimer’s disease and other dementia, and infectious and autoimmune diseases.1,2,3,4,5,6,7,8
Advances in the clinical measurement of inflammation and the immune response have ushered in a new era of thinking about ways that immunomodulation might affect chronic diseases and outcomes.9 The benefits of integrative approaches for managing inflammation can be measured, and treatment can be better targeted and quality of life improved.
There is a long history of drug development directed at inflammation; these drugs have advanced from steroid therapy to nonsteroidal anti-inflammatories, to broad-spectrum immunosuppressives to targeted anticytokine agents, offering new and powerful options for intervening in inflammatory conditions.10
This explosion in the number of drugs targeting various parts of the inflammatory process is testament to the complexity of inflammatory pathways. It has also led to a growing understanding of the many ways that integrative and preventive approaches might be used for better control and outcomes in inflammatory disorders. Food, fitness, physical activity, sleep, supplements, and stress have all been shown to affect levels of inflammation and can be used as complementary approaches to help reduce inflammation.11,12,13,14,15,16
But first, what is inflammation and why is it so common?
The most common triggers of inflammation are infection and injury; both require a response of the immune system to invoke healing. That immune response produces the classic clinical signs of inflammation, often described as rubor, calor, tumor, and dolor—redness, heat, swelling, and pain. Redness and warmth result from the increase in blood flow triggered by cytokines that cause both vasodilation and growth of new capillaries (angiogenesis). Increased permeability of capillaries leads to accumulation of fluid (swelling) and the release of pain mediators like prostaglandins, substance P, histamine, and bradykinin contribute to causing pain (dolor). The accumulation of these numerous inflammatory mediators has been coined the “inflammatory soup.”17
These clinical features are the hallmarks of inflammation and in most cases are essential to the healing process. Increase in blood flow helps to dilute the number of pathogens, while bringing more leukocytes and macrophages to the area to help control infection. Pain and swelling are likely a protective response to help immobilize the site and reduce the damaging effects of trauma to the healing process.
The intricate deployment of the inflammatory response is a complex and dynamic process, and there are a variety of possible responses from minor, local reactions to full-blown and life-threatening systemic reactions in anaphylaxis, sepsis, or multisystem organ failure. The wide range of immune response means that control of the inflammatory cascade is also critical; it is possible that the immune response might be inadequate, or at times excessive. The response of our immune system should match the perceived threat, as both inadequate and excessive responses carry serious risks.18
Excessive or inappropriate immune responses, themselves, are known to cause disease or complications in such conditions as influenza and other viral syndromes, allergy and hypersensitivity, and in autoimmune diseases.19 More recently, inflammation has been found to play a role in acute coronary syndromes,1 stroke,20 type 2 diabetes,3 Alzheimer’s disease,5 obesity,21,22 macular degeneration,7 atrial fibrillation,23,24 aneurysms,25,26,27 and many other noninfectious conditions.28,29,30,31,32,33 These may represent instances in which inappropriate or dysregulated immune responses can cause serious problems.
Like so many processes in the body, the inflammatory response—the healing stress response of our immune system—needs to be appropriate for the actual threat. It is a Goldilocks situation—the immune response cannot be too little or too big; it needs to be “just right.” Regulation of the immune response is as important as its speed and capabilities.
The immune system comprises a wide range of cells, tissues, and organs, each with specific functions in immunity and inflammation. The immune system has both built-in (innate) and learned (adaptive) immune responses. Immune responses can be both cellular, for example macrophages and cytotoxic cells, and humoral, conveyed by chemical structures such as antibodies, complement cascade, and cytokines (Box 17.1).
Inflammation is usually set into motion by local factors that trigger release of proinflammatory cytokines by tissue macrophages, neutrophils, or lymphocytes responding to local infection, injury, or ischemia, most often. These proinflammatory cytokines include interleukin 1-beta, TNF-α (tumor necrosis factor alpha), and interleukin-6, which are produced after the activation of nuclear factor kappa B (NF-kB).
The NF-kB family of transcription factors plays a crucial role in regulation of the inflammatory response. Normally, NF-kB is held in an inactive state in the cytosol, and translocates to the nucleus of the cell when triggered to initiate cytokine transcription.34,35 Regulation of nuclear factors in the NF-kB family and its movement from nuclear DNA back to the cytosol is also involved in down-regulation of the inflammatory response. NF-kB has been found in almost all cells and can bind to many genes involved in a broad range of cellular, immune, and inflammatory processes. Along with eicosanoids, ROI (reactive oxygen intermediates), TNF-α, and NF-kB can not only escalate inflammation but also contribute to its resolution and are pivotal in the overall regulation of the immune response.
Other important mediators of inflammation include prostaglandins, leukotrienes, and lipoxins; histamine; the complement system; the kinin-kallikrein system; nitric oxide (NO); and the clotting system. Key regulatory cytokines include Transforming Growth Factor (TGF)-beta and interleukin-10.
Prostaglandins are also key regulators of the immune response. The four principal prostaglandins, derived from cyclooxygenase (COX) and arachidonic acid are PGE2, PGI2, PGD2, and PGF2a.36 The COX inhibitors, targeting the two isoforms of COX are an effective class of nonsteroidal anti-inflammatory agents.
Nearly all cells in the body produce prostaglandins, and at least 10 types of receptors are identified, controlling a wide range of effects in different tissues.
Prostaglandin E2 is the most widely produced prostaglandin and it is involved in the vasodilation, swelling, and pain—rubor, tumor, and dolor—of inflammation. It is a small molecule that exerts control over macrophages, granulocytes, mast cells, dendritic cells, and natural killer cells as well as B-cells.37
Prostaglandin I2 is produced mainly in the cells of the cardiovascular system, endothelial cells, vascular smooth muscle cells, and endothelial progenitor cells. It is a vasodilator and inhibitor of platelet aggregation and leukocyte adhesion. Prostaglandin D2 is found in the central nervous system involved in pain perception, and in peripheral tissues, primarily mast cells.37
Cellular components used in the inflammatory response (Table 17.1) can also be regulated in many ways, for example the Treg CD4 T-cells responsible for controlling the immune effects of Th helper cells.38 T-helper cells include Th1 and Th2 cells, which release different cytokines; Th1 produce interferon-gamma, IL-2, TNF-beta, and Th2 produce IL-4, IL-5, IL-10, and IL-13.39
Table 17.1 Components of the Cellular Immune System
Cytotoxic T cells
Natural killer cells
CD4 + helper
If regulatory measures are insufficient or there is inappropriate or excessive reaction of the immune system, the result is hypersensitivity or autoimmunity. Four types of hypersensitivity reactions are characterized based on their clinical patterns. Type I is acute IgE-mediated and includes anaphylaxis, asthma, eczema, and urticaria, and the basis for skin prick allergy testing. Type 2 is IgG-mediated cytotoxic cell-mediated immunity, for example in transfusion reactions. Type 3 immune complex–mediated hypersensitivity for example in glomerulonephritis, and Type 4 delayed cell-mediated hypersensitivity from sensitized Th1 cells, for example in the PPD skin reaction.
Measuring inflammation is helpful in several ways. It allows for monitoring disease activity and clinical response, can help identify when a remission has been achieved, and can help guide duration of therapy.42,43,44 It can also confirm the effectiveness or ineffectiveness of drug therapy.41
Since inflammation precedes symptoms, measuring inflammation might provide some predictive value, which could help to improve prevention. An example is the JUPITER trial, in which C-RP (C-reactive protein) levels predicted the risk of subsequent heart attack and stroke, and successful lowering of C-RP reduced heart attack and strokes.40
In Rome between 30 and 45 AD, Aulus Celsus first described the four cardinal signs of redness, warmth, swelling and pain.45 Ever since, we have been finding new ways of describing and measuring inflammation. And to this day, healthcare providers rely on these physical signs for diagnosis. But visible redness, warmth, swelling, and pain are often later signs of an underlying infection or inflammatory process. Inflammation can often be detected before symptoms develop by measuring inflammatory markers in the blood.
The most basic and often requested is the WBC, or white blood count. Peripheral blood white blood counts (usually expressed in thousands per microliter) have long been used to assess the severity of infections and the response to therapy. Surgical decisions, antibiotic therapy, transplant rejection, transfusion reactions, and cancer care all rely on the white blood count for critical decision-making.
In 1897 the Polish doctor Edmund Biernacki discovered that red blood cells dropped or sedimented more quickly in the presence of inflammation, leading to the erythrocyte sedimentation rate test, aka ESR or “sed rate.”49 The ESR is useful in the diagnosis and monitoring of rheumatic diseases rheumatoid arthritis, polymyalgia rheumatic, temporal arteritis, and inflammatory bowel disease, among others. The ESR has in many cases been supplanted by wider-spread use of the C-RP test because of its increased sensitivity.
Discovered in 1930 by Tillett and Francis, C-RP was named initially as a substance reacting with the “C” carbohydrate antigen of Pneumococcus. More sensitive assays using nephelometry became available around 2000 measuring levels as low as 0.04 mg/L, leading to numerous studies of low-level inflammation and cardiovascular disease. These studies have popularized the notion of “cardiac” C-RP, though the term is misleading, since C-RP is not specific to the cardiovascular system. The “highly sensitive C-RP” refers to the same assay, providing sensitivity as low as 0.04 mg/L.
Since 1995, numerous studies have linked the presence of low-level inflammation as measured by C-RP with a variety of disorders, the list of which includes:
• Type 2 diabetes7
• Macular degeneration7
• Alzheimer’s disease and other forms of dementia5
• Colon cancer51
Some large-scale studies have also supported the idea that therapeutic intervention with treatment designed to lower C-RP also produced improved clinical outcomes, as shown in the JUPITER study involving almost 18,000 participants.40 The study results supported the idea of lowering C-RP as a form of primary prevention for men and women over age 50. These studies have reframed the target ranges for C-RP levels, which now are generally accepted as:
*Clinicians reviewing results from laboratories reporting units in mg/dL will need to multiply results by 10 for comparisons with mg/L results.
Beyond WBC, ESR, and C-RP, there are also other laboratory measures and findings with inflammation. Myeloperoxidase (MPO) is an enzyme found predominantly in granulocytes, where it is used in bacterial defenses. Similar to C-RP, elevated levels of MPO have also been shown to predict future acute coronary syndromes.55
Deriving their name from the origins of the root for “cell” and “movement,” cytokines are chemicals that were initially found to direct the movement of cells. Cytokines are “trophic” for mobile cells, meaning they act as a homing signal for macrophages, neutrophils, and the like. Some cytokines are also growth factors for certain cell lines, or for regulating the immune response. Cytokines can be produced in virtually any cell, and are primarily used for communication—cell signaling for cells to “speak” to one another.
Cytokines include chemicals such as the interferons, interleukins, the TNF-α family, mesenchymal growth factors, stem cell factors, adipokines, and neurotrophic factors.56 At least a hundred cytokines have been identified, and most cells have the ability to produce and react in some way to cytokines. That is different from the more specialized hormones, for example, which are produced by only a few cells specialized for that purpose.
Cytokines are primarily involved in inflammation and the immune response, but cytokines have also been found to play a role in embryogenesis. Cytokines can be chemokines (chemical attractants), interleukins (targeting leukocytes), interferons (targeting viruses), proinflammatory (e.g., TNF-α family), or growth factors (e.g., hematopoietic growth factors G-CSF, erythropoietin, and others).
Cytokines that increase the inflammatory process include the TNF-α, IL-6 and IL-1beta among others. There are also anti-inflammatory cytokines like IL-1 receptor antagonist, IL-4, IL-10, IL-11, and IL-13.57
Measurement of cytokines is becoming an increasingly useful tool in the assessment and management of inflammatory disorders. Multiplex cytokine panels have been developed to aid in clinical assessment of rheumatic disorders, for example, the Vectra-DA panel and others.58,59
In addition to these markers, which are thought to be somewhat specific for inflammation, there are also a number of elevated markers that are less specific, and these could be lumped together as “acute phase reactants.” Acute phase reactants are proteins that increase at least 25% in the blood in response to inflammation, but they have other primary functions in the body. An example would be ferritin, which goes up during acute inflammation, but is normally involved with iron storage. Another example would be fibrinogen (clotting), ceruloplasmin (copper transport), serum amyloid A (cholesterol transport), or alpha-2-macroglobulin (enzyme regulation).
It is worth reinforcing that any markers of inflammation are nonspecific, in that none identify the cause of inflammation, nor its location, nor do they identify a specific treatment. They are signs of a problem, but they are not specific for any particular problem. They can provide some predictive value, but the timeline of endpoints and symptoms is not easily discerned. Unless the specific cause of inflammation is known, measurement of inflammation can cause undue anxiety and fear about risk without having specific preventive strategies in place; so how can assessment of inflammation be more helpful?
There are several ways that imaging inflammation can be used clinically, where it can help to diagnose its source or determine the best treatment. In some conditions, imaging inflammation is being used for early diagnosis, for example the use of FDG PET-CT imaging in neurologic disease including Alzheimer’s disease, cardiovascular disease, cancer, and inflammatory disorders.60 Improved tracers and markers could help to better understand different disease processes and pathways.
Traditional forms of imaging, such as X-ray, CT, MRI, and ultrasound, all show typical and pathologic signs of inflammation and are widely used in the diagnosis of inflammatory conditions such as abscesses, diverticulitis, arthritis, tendonitis, fractures, cancer, or appendicitis.
Some integrative practitioners have championed the use of thermography for noninvasive screening for breast cancer, for example.61 By detecting the increased heat from localized inflammation and blood flow, thermography uses the calor feature of inflammation to detect tumors. It is unknown how thermography screening compares with mammography,62 although recent concerns about the increasing oversensitivity of mammography should lead to a deeper investigation of alternative screening in breast cancer.
Blood measures combined with selective imaging in certain conditions might give the most insight. Understanding the possible causes of inflammation should help inform decisions about whether to consider imaging.
In order to address the specific cause of inflammation most successfully, it is helpful to know as best we can, what the source, the site, and the mechanism of inflammation might be. That way, we can make better decisions about treatment and understand how to monitor therapy. Causes of inflammation could be categorized as follows:
1. Well-recognized causes:
2. Other less-recognized causes:
Regardless of the cause of inflammation, it can be either acute or become chronic. The immune and healing responses are different in their early and late manifestations.
Inflammation and Cancer
The connection between inflammation and cancer is complex. Chronic inflammation is one known risk of cancer, which is seen not uncommonly in chronic inflammatory bowel disease (IBD) or the development of mesothelioma lung cancer years after asbestos exposure. Levels of inflammation have been found to be elevated prior to the development of colon cancer, suggesting a role for inflammation in colon carcinogenesis.4 But levels of inflammation are also increased in people with advanced cancer, presumably representing the immune response to cancer itself.
To make matters more confusing, the immune response may in some ways contribute to the growth and spread of cancer through the production and release of angiogenic substances such as VEGF that unintentionally increase blood and nutrient flow into tumors.80,81
In these ways, inflammation can contribute to the initiation, propagation, and spread of cancer. Knowing the level of inflammation does not necessarily predict the presence of cancer, or necessarily its stage or grade.
The treatment of inflammation offers great opportunities because of the many locations to impact the inflammatory cascade. Successful treatment requires targeting the cause of inflammation; antibiotics will not cure cancer, and a baby aspirin will not treat obstructive sleep apnea.
On the other hand, regardless of the source of inflammation, it is often imperative to protect against the complications of having it. If you cannot immediately resolve the obesity issue, it is crucial to guard against heart attack and stroke in the meantime.
So there are specific ways of targeting the cause of inflammation, and more general ways of reducing the overall level of inflammation that would both improve symptoms and outcomes.
Since its synthesis in 1853 and commercialization as “Aspirin” by Bayer, acetylsalicylic acid is still in widespread use primarily in prophylaxis against cardiovascular events.82 Prophylactic benefits of low-dose aspirin appear to be working through its COX-1 inhibition and antiplatelet effects rather than lowering C-RP.83
Corticosteroid medications have long been the mainstay of managing chronic inflammatory disorders from asthma to rheumatic and other autoimmune diseases. Corticosteroids have broad immunosuppressive effects that affect cell-mediated immunity as well as working by suppressing transcription of genes involved in the inflammatory process.84 Unfortunately, side effects and long-term adverse effects severely compromise the value of corticosteroids in the management of chronic inflammation.
More targeted therapies offer the potential of controlling inflammation potentially with fewer adverse effects. Discovery of cytokines and understanding their role has led to more targeted anti-inflammatory therapies that are now becoming the mainstay for many challenging inflammatory conditions.
In 1998, Enbrel (etanercept) was the first biologic anticytokine drug released for commercial use in the treatment of rheumatoid arthritis. Designed as a decoy TNF-α receptor, etanercept bound and inactivated TNF-α. Since the successful release of Enbrel, there has been an explosion in biologic drugs targeting cytokines or other components of the inflammatory pathway. Approved indications for the use of Enbrel have broadened to include psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis.
A second TNF-α-blocking biologic, Remicade (infliximab) was FDA-approved and released in 2001 for the treatment of rheumatoid arthritis, and subsequently broadened its indications for use in inflammatory bowel diseases (Crohn’s disease and ulcerative colitis), ankylosing spondylitis, and severe plaque psoriasis.
Growth in the immunomodulating biologic drugs has accelerated, and biologics now account for 17% of the total global pharmaceutical revenues.85 Anti-TNF-α-blocking biologics now include Enbrel, Remicade, Humira, Cimzia, Inflectra, Ridaura, and Simponi. Specific anticytokine therapy now also includes specific IL-6-blocking agents (e.g., Actemra, released in July 2014, for treatment of rheumatoid arthritis in the United States). Newer biologics are now also targeting IL-1 (e.g., Kineret), and cell-mediated immunity (Orencia). Consentyx was designed to block IL-17A in psoriasis and uveitis. Xeljanz is approved as an inhibitor of JAK1 and JAK3 signaling pathway enzymes. The availability of biologics for specific cancers is also growing rapidly; for example, Rituxan in the treatment of lymphomas as well as some autoimmune diseases.
Indications for the use of targeted biologic drugs has grown from the prototype of rheumatoid arthritis to include a wide range of autoimmune and neoplastic disorders including psoriatic arthritis, ankylosing spondylitis, psoriasis, inflammatory bowel disease, systemic lupus erythematosus, scleroderma and progressive systemic sclerosis, vasculitis, and giant-cell arteritis.86
Herbal and OTC products have also been shown to have some activity in inhibiting TNF-α or other inflammatory cytokines.
Turmeric (Curcuma longa) has a long history of use as a spice as well as a medicinal herb. Curcumin is the extract of turmeric, and has a number of potential mechanisms to explain its anti-inflammatory effect. Curcumin may act by blocking or interfering with TNF-α60 or other proinflammatory cytokines such as IL-1B and IL-687 or by blocking NF-kB activation.88 Clinical studies of curcumin in humans have shown promising results. Curcumin seems to be a beneficial adjunct in the treatment of osteoarthritis89,90 as well as possibly rheumatoid arthritis.91
Curcumin may also have an effect in reducing levels of some inflammatory cytokines—IL-1β, IL-4, and VEGF, at doses of 1 gram daily, in obese individuals.92
In patients undergoing chemotherapy for solid tumors, “boosted bioavailable” curcumin supplements in doses of 180 mg per day improved levels of inflammatory cytokines TNF-α, TGFβ, IL-6, and substance P, and improved quality of life scores.93
It is recognized that bioavailability of oral curcumin is quite, poor,94 but processing methods might improve its bioavailability and effectiveness.95,96There may also be gender differences in absorption of curcumin, with women absorbing relatively more.97
Curcumin supplements dramatically reduce the chance of myocardial infarction in patients undergoing coronary artery bypass surgery (CABG) and significantly reduce C-RP and markers of oxidative stress postoperatively.101
Milk thistle (silymarin), resveratrol, epigallocatechin gallate (green tea extract), mangostin, other polyphenols have displayed inhibitory activity of TNF-α,102 however there are few controlled clinical trials examining anti-inflammatory effects in humans.
Silymarin may help reduce levels of C-RP in patients with type 2 diabetes103 and in one study significantly improved survival in cirrhosis104 but did not seem to help normalize liver enzymes in some hepatitis C patients.105
Herbal products have some evidence for inhibiting other proinflammatory cytokines. Herbal IL-6 inhibitors include green tea extract (epigallocatechin gallate)106 and andrographolide (Andrographis paniculata).107,108
There has been much recent interest in cannabinoids and their immune and anti-inflammatory properties, with particular interest in their use in chronic pain and inflammatory conditions. Cannabinoids are a family of compounds mediating their effects via the cannabinoid receptor. Two receptors, CB1 and CB2, have been identified in the brain and the immune system, respectively. Cannabinoids work in part by down-regulating T-cells, but also by reducing cytokine and chemokine production.112 Preliminary studies show some benefits in inflammatory bowel disease,113 however a consistent anti-inflammatory effect has not been demonstrated.
Integrative Approaches to Reducing Inflammation
While medications and supplements can be important tools in the management of inflammatory conditions, there are also a number of successful integrative and lifestyle methods of achieving similar benefits.
Perhaps one of the most important ways that exercise exerts its pleomorphic benefits is through its anti-inflammatory effects. Moderate aerobic exercise has been shown to consistently reduce inflammation over time.114,115 Short-term exercise produces a transient increase in inflammation, which over time results in lower levels of systemic inflammation.116 There is some conflict in the literature as to whether exercise has an independent effect on reducing inflammation, or only has the effect if weight loss occurs. Some studies suggest that exercise improves inflammation even without weight loss117,118 (the so-called fat but fit), while others suggest that exercise without weight loss does not lower C-RP.119
Short-term responses to high-intensity exercise consistently show increases in inflammation and C-RP. Following intense exercise, like a marathon, C-RP levels have been found to rise 266% before returning to baseline by 48 hours.120 Long-term responses to moderate exercise consistently produce a drop in levels of C-RP.116
Weight Loss and Diet
Weight loss is a strong lifestyle approach for controlling inflammation. Several studies have linked obesity and overweight with increased inflammatory markers,21,121 and weight loss has also been shown to help reduce them.115,122 Inflammation may represent a mechanism where obesity accelerates cardiovascular disease, or cancer. Obesity as a chronic inflammatory disease may help explain the many complications of obesity, from type 2 diabetes to hypertension, cancer, asthma, stroke, and heart attack.123
Weight loss has been shown to help reduce the risk of those same conditions. The adverse effects of obesity are numerous, and there are numerous mechanisms by which obesity contributes to the acceleration of illness. Inflammation is but one of these mechanisms, but is perhaps one we have more control of.
One of the dietary measures often found to be most helpful and successful with weight loss includes increasing intake of dietary fiber.124,125 Increasing dietary fiber intake has also been found to help reduce inflammatory markers.126,127,128 Both insoluble and soluble fiber are helpful, although supplements of predominantly soluble fiber may not be sufficient as foods such as legumes, fruits, and berries that have both soluble and insoluble fiber.129,130
Another common piece of advice for healthy eating and weight loss is to eat more fish and omega-3 fish oils. Consumption of essential omega-3 fish oils EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) either through consumption of fish131,132 or fish oil supplements133 appear to have a beneficial effect in lowering C-RP. Clinically, fish oil supplements have shown benefits in rheumatoid arthritis,134 with significant improvement in symptoms and additive effects with standard therapies.135
Surprising news perhaps is the effect of moderate alcohol consumption on inflammatory markers. Unlike smoking, which raises C-RP, moderate alcohol consumption lowers it.136,137 The problem is that it seems to take at least moderate alcohol consumption to significantly impact C-RP; a 5-ounce glass of red wine daily may not be enough.138 Unfortunately, at the intakes needed to effectively lower C-RP, secondary problems of alcohol excess may occur, including dependency, addiction, accidents, and the increased rates of cancer found especially for reproductive cancers.139 For these reasons, and because of the common tendency to imbibe more than the recommended amount, it is not prudent to recommend alcohol use for controlling inflammation or lowering C-RP.
Sleep, Stress, Mood, Meditation, and Massage
Sleep deprivation increases inflammation, whether it results from a medical sleep disorder such as obstructive sleep apnea, or from menopause, or simply from self-imposed sleep restriction.14,31 The human body needs a certain amount of sleep, and getting less than it needs is stressful. Stress from almost any source produces the stress response of the immune system—inflammation. Emotional stress has a physical reaction, also, and that is inflammation. Techniques used to help relieve stress, to improve the quality of sleep, and to relieve anxiety, anger, and despair also help to lower inflammation.
Some of the most helpful techniques in relieving stress are yoga, breathing exercises, meditation, and massage and other bodywork. Yoga has a long tradition with millions of practitioners, and there are many different techniques and styles of yoga practice, from hot Bikram yoga to strenuous Ashtanga or calming restorative yoga. While the forms of yoga may be quite different, the elements of breathing, focus, and mindfulness extend across all of them. Extensive trials of different yoga techniques have not been done, but research suggests yoga and breathing techniques have a beneficial effect on reducing inflammation.
A trial of 218 volunteers studied baseline levels of cytokines TNF-α and IL-6 levels in a group of regular yoga practitioners (at least an hour daily for over 5 years) and found lower baseline inflammatory cytokine levels compared with age and gender-matched controls.140 Yoga was also found to be beneficial in a group of women breast cancer survivors, who displayed lower inflammatory markers over 3 months than similar survivors who were not practicing yoga.141 A recent innovative trial looked at salivary cytokine and suggested a benefit of yogic breathing practices in reducing inflammation.142
Mindfulness-based meditation practices are another nonpharmacologic way of reducing inflammation. In a recent small study comparing mindfulness-based meditation with relaxation, lower levels of proinflammatory IL-6 were found in meditators.143 A meta-analysis of mindfulness meditation and the immune system found possible but heterogeneous effects on reducing inflammatory markers.144 A novel study of the effects of mindfulness meditation on the stress response showed that meditators had lower levels of inflammatory TNF-α and IL-8 in blister fluid evoked by capsaicin application. The study suggested that mindfulness-based meditation might help dampen the inflammatory response to emotional and physical stress and inflammation.145
Massage is a modality often recommended for treating pain and inflammation, and yet studies on its physiologic effects are limited. A bold study in 2012 actually took muscle biopsies in 11 volunteers immediately after massage and 2.5 hours later. Findings suggested an anti-inflammatory effect of massage that was felt to be mediated by NF-kB and down-regulation of TNF-α, IL-6, and heat shock protein 27. This preliminary study suggested a mechanism by which massage might exert its anti-inflammatory effects.146
Acupuncture is another commonly recommended modality for addressing pain and inflammatory conditions. Despite a long history of clinical use around the world, mechanisms for the effects of acupuncture on pain and inflammation are still largely theoretical.147,148,149 There are a large number and variety of clinical trials of acupuncture. A 2012 meta-analysis of 29 randomized-controlled trials of acupuncture in chronic pain showed acupuncture to be superior to sham treatment or no-acupuncture control conditions.150 Results of these trials have raised some questions, however, because of the partial responses to “sham” acupuncture in controlled trials. Clearly more work is needed to explain the clinical effects of acupuncture, its mechanism, and for what conditions it provides clear benefits.
Perhaps the most underappreciated effect on inflammation is the effect of social relationships. Humans are social creatures, and we know that relationships are important for both the quality and quantity of human life. One of the ways that social relationships might improve health could be through reducing inflammation. A comprehensive review of the interplay between relationships and inflammation reveals close parallels between the quality of important relationships and levels of inflammatory cytokines, especially IL-6, TNF-α and C-RP.151
The authors concluded: “Close relationships matter. Not only do close relationships shape people’s emotions, they affect the very physiological processes that underlie disease. Close relationships across the lifespan contribute to elevated inflammation—now a well-regarded risk factor for disease.”
The awareness, assessment, and management of inflammation has finally come of age—both for prevention and as a focus of treatment it has improved outcomes and quality of life in chronic diseases. Science has improved our understanding of the many causes of inflammation and how it affects health. Great progress has been made with therapeutic options for treating inflammation, and those options are becoming more targeted and more powerful as we learn how to impact different points on the inflammatory cascade. Many questions remain for future investigation: Can the immune response be guided to improve outcomes in infectious and inflammatory diseases without adverse effects or contributing to cancer growth? What are the negative effects of reducing inflammation? What are the best lifestyle strategies for controlling inflammation and extending healthy lifespan? Are there benefits to mild immunosuppression in the aging population to improve age-related disorders and inflammatory diseases? Is lifestyle superior to medications or are they complementary? Do anti-inflammatory therapies extend life or reduce morbidity?
Hopefully with advances in the understanding and measurement of inflammation, these answers will be forthcoming soon!
1. Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 2004;351:2599–2610.Find this resource:
2. Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med 2011;364:656–665.Find this resource:
3. Pradhan AD, Manson JE, Rifai N. C-Reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286(3):327–334.Find this resource:
4. Erlinger TP, Platz EA, Rifai N. C-reactive protein and the risk of incident colorectal cancer. JAMA 2004;291(5):585–590.Find this resource:
5. Engelhart MJ, Geerlings MI, Meijer J, et al. Inflammatory proteins in plasma and the risk of dementia: the Rotterdam Study. Arch Neurol 2004;61(5):668–672.Find this resource:
6. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420(6917): 860–867.Find this resource:
8. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events. Circulation 2003;107: 391–397.Find this resource:
9. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001;103:1813–1818.Find this resource:
10. Rider P, Carmi Y, Cohen I. Biologics for targeting inflammatory cytokines, clinical uses, and limitations. Int J Cell Biology 2016;2016:Article ID 9259646.Find this resource:
11. Ma Y, Griffith JA, Chasan-Taber L, et al. Association between dietary fiber and serum C-reactive protein. Am J Clin Nutr 2006; 83(4):760–766.Find this resource:
12. Sadeghipour HR, Rahnama A, Salesi M, Rahnama N, Mojtahedi H. Relationship between C-reactive protein and physical fitness, physical activity, obesity and selected cardiovascular risk factors in schoolchildren. Int J Prev Med 2010;1(4):242–246.Find this resource:
13. Kasapis C, Thompson PD. The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review. J Am Coll Cardiol 2005;45(10):1563–1569.Find this resource:
14. Meier-Ewert HK, Ridker PM, Rifai N, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol 2004;43(4):678–683.Find this resource:
15. Carroll MF, Schade DS. Timing of antioxidant vitamin ingestion alters postprandial proatherogenic serum markers. Circulation 2003;108(1):24–31.Find this resource:
16. Wium-Andersen MK, Ørsted DD, Nielsen SF, Nordestgaard BG. Elevated C-reactive protein levels, psychological distress, and depression in 73,131 individuals. JAMA Psychiatry 2013;70(2):176–184.Find this resource:
17. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell 2009;139(2):267–284.Find this resource:
18. Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008;8(10):776–787.Find this resource:
19. Iwasaki A, Pillai PS. Innate immunity to influenza virus infection. Nat Rev Immunol 2014;14(5):315–328.Find this resource:
20. Cao JJ, Thach C, Manolio TA, et al. C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. Circulation 2003;108:166–170.Find this resource:
21. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB, Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999;282(22): 2131–2135.Find this resource:
22. Aronson D, Bartha P, Zinder O, et al. Obesity is the major determinant of elevated C-reactive protein in subjects with the metabolic syndrome. Int J Obes Relat Metab Disord 2004;28(5):674–679.Find this resource:
23. Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients with atrial arrhythmias. inflammatory mechanisms and persistence of atrial fibrillation. Circulation 2001;104:2886–2891.Find this resource:
25. Norman P, Spencer CA, Lawrence-Brown MM, Jamrozik K. C-Reactive Protein Levels and the expansion of screen-detected abdominal aortic aneurysms in men. Circulation 2004;110:862–866.Find this resource:
26. C-reactive protein (CRP) elevation in patients with abdominal aortic aneurysm is independent of the most important CRP genetic polymorphism. J Vasc Surg 2009;49(1):178–184.Find this resource:
27. De Haro J, Bleda S, Acin F. C-reactive protein predicts aortic aneurysmal disease progression after endovascular repair. Int J Cardiol 2016;202:701–706.Find this resource:
28. Gosling P, Dickson GR. Serum C-reactive protein in patients with serious trauma. Injury 1992;23(7):483–486.Find this resource:
29. Mok CC, Birmingham DJ, Ho LY, Hebert LA, Rovin BH. High-sensitivity C-reactive protein, disease activity, and cardiovascular risk factors in systemic lupus erythematosus. Arthritis Care Res 2013;65:441–447.Find this resource:
30. Ma Y, Chiriboga DE, Pagoto SL, et al. Association between depression and C-reactive protein. Cardiol Res Pract 2011;2011:286509.Find this resource:
31. Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, Somers VK. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002;105(21):2462–2464.Find this resource:
32. Galez D, Dodig S, Raos M, Nogalo B. C-reactive protein in children with asthma and allergic rhinitis. Biochemia Medica 2006;16(2):163–169.Find this resource:
33. Aleem S, Masood Q, Hassan I. Correlation of C-reactive protein levels with severity of chronic urticaria. Indian J Dermatol 2014;59(6):636.Find this resource:
34. Oeckinghaus A, Ghosh S. The NF-κB family of transcription factors and its regulation. CSH Perspect Biol 2009;1(4):a000034.Find this resource:
35. Shih R-H, Wang C-Y, Yang C-M. NF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci 2015;8:77.Find this resource:
36. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscl Throm Vas 2011;31(5):986–1000.Find this resource:
37. Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol (Baltimore, Md.: 1950) 2012;188(1):21–28.Find this resource:
38. Corthay A. How do regulatory T cells work? Scand J Immunol 2009;70(4): 326–336.Find this resource:
39. Romagnani S. Th1/Th2 cells. Inflamm Bowel Dis 1999;5(4):285–294. Review.Find this resource:
40. Ridker PM, Danielson E, Fonseca FAH, et al., for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–2207.Find this resource:
41. Heiro M, Helenius H, Sundell J, et al. Utility of serum C-reactive protein in assessing the outcome of infective endocarditis. Eur Heart J 2005;26:1873–1881.Find this resource:
42. Shrotriya S, Walsh D, Bennani-Baiti N, Thomas S, Lorton C. C-reactive protein is an important biomarker for prognosis tumor recurrence and treatment response in adult solid tumors: a systematic review. PLoS One 2015;10(12):e0143080.Find this resource:
43. Leuzzi G, Galeone C, Gisabella M, et al. Baseline C-reactive protein level predicts survival of early-stage lung cancer: evidence from a systematic review and meta-analysis. Tumori 2016;102(5):441–449.Find this resource:
44. Køstner AH, Kersten C, Löwenmark T, et al. The prognostic role of systemic inflammation in patients undergoing resection of colorectal liver metastases: C-reactive protein (CRP) is a strong negative prognostic biomarker. J Surg Oncol 2016;114(7):895–899.Find this resource:
45. Granger DN, Senchenkova E.Inflammation and the Microcirculation. San Rafael, CA: Morgan & Claypool Life Sciences; 2010.Find this resource:
46. Margolis KL, Manson JE, Greenland P, et al; Women’s Health Initiative Research Group. Leukocyte count as a predictor of cardiovascular events and mortality in postmenopausal women: the Women’s Health Initiative Observational Study. Arch Intern Med 2005;165(5):500–508.Find this resource:
47. Madjid M, Awan I, Willerson JT, Casscells SW. Leukocyte count and coronary heart disease. J Am Coll Cardiol 2004;44(10):1945–1956.Find this resource:
48. Haim M, Boyko V, Goldbourt U, Battler A, Behar S. Predictive value of elevated white blood cell count in patients with preexisting coronary heart disease: the Bezafibrate Infarction Prevention Study. Arch Intern Med 2004;164(4):433–439.Find this resource:
49. Grzybowski A, Sak J. Edmund Biernacki (1866–1911): discoverer of the erythrocyte sedimentation rate; on the 100th anniversary of his death. Clin Dermatol 2011;29(6):697–703.Find this resource:
50. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. C-reactive protein and the risk of developing hypertension. JAMA 2003;290(22):2945–2951.Find this resource:
51. Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ. C-reactive protein and the risk of incident colorectal cancer. JAMA 2004;291(5):585–590.Find this resource:
52. Aref H, Refaat S. CRP evaluation in non-small cell lung cancer. Egypt J Chest Diseases and Tuberculosis 2014;63(3):717–722.Find this resource:
53. Vagulienė N, Žemaitis M, Miliauskas S, Urbonienė D, Šitkauskienė B, Sakalauskas R. Comparison of C-reactive protein levels in patients with lung cancer and chronic obstructive pulmonary disease. Medicina (Kaunas) 2011;47(8):421–427. Epub 2011 Nov 18.Find this resource:
54. Alifano M, Falcoz PE, Seegers V, et al. Preresection serum C-reactive protein measurement and survival among patients with resectable non-small cell lung cancer. J Thorac Cardiovasc Surg 2011;142(5):1161–1167.Find this resource:
55. Meuwese MC, Stroes ES, Hazen SL, et al. Serum myeloperoxidase levels are associated with the future risk of coronary artery disease in apparently healthy individuals: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol 2007;50(2):159–165. Epub 2007 Jun 21.Find this resource:
56. Dinarello CA. Historical review of cytokines. Eur J Immunol 2007;37(Suppl 1):S34–S45.Find this resource:
57. Zhang J-M, An J. Cytokines, inflammation and pain. Int Anesthesiol Clin 2007;45(2):27–37.Find this resource:
58. Centola M, Cavet G, Shen Y, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One 2013;8(4):e60635.Find this resource:
59. Curtis JR, van der Helm-van Mil AH, Knevel R, et al. Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity. Arthritis Care Res 2012;64(12):1794–1803.Find this resource:
61. Fitzgerald A, Berentson-Shaw J. Thermography as a screening and diagnostic tool: a systematic review. N Z Med J 2012;125(1351):80–91.Find this resource:
62. Mainiero MB, Lourenco A, Mahoney MC, et al. ACR appropriateness criteria breast cancer screening. J Am Coll Radiol 2013;10(1):11–14.Find this resource:
63. Meier-Ewert HK, Ridker PM, Rifai N, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol 2004;43(4):678–683.Find this resource:
64. Wu SQ, Liao QC, Xu XX, Sun L, Wang J, Chen R. Effect of CPAP therapy on C-reactive protein and cognitive impairment in patients with obstructive sleep apnea hypopnea syndrome. Sleep Breath 2016;20(4):1185–1192.Find this resource:
65. Wu WT, Tsai SS, Shih TS, et al. The impact of obstructive sleep apnea on high-sensitivity C-reactive protein in subjects with or without metabolic syndrome. Sleep Breath 2015;19(4):1449–1457.Find this resource:
66. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999;282(22):2131–2135.Find this resource:
67. Raz O, Steinvil A, Berliner S, Rosenzweig T, Justo D, Shapira I. The effect of two iso-caloric meals containing equal amounts of fats with a different fat composition on the inflammatory and metabolic markers in apparently healthy volunteers. J Inflamm (London, England) 2013;10:3.Find this resource:
68. Carroll MF, Schade DS. Timing of antioxidant vitamin ingestion alters postprandial proatherogenic serum markers. Circulation 2003;108(1):24–31.Find this resource:
69. Kobrosly R, van Wijngaarden E. Associations between immunologic, inflammatory, and oxidative stress markers with severity of depressive symptoms: an analysis of the 2005–2006 National Health and Nutrition Examination Survey. Neurotoxicology 2010;31(1):126–133. doi: 10.1016/j.neuro.2009.10.005.Find this resource:
70. Silić A, Karlović D, Serretti A. Increased inflammation and lower platelet 5-HT in depression with metabolic syndrome. J Affect Disord 2012;141(1):72–78. doi: 10.1016/j.jad.2012.02.019.Find this resource:
71. Bremmer MA, Beekman AT, Deeg DJ, et al. Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord 2008;106(3):249–255.Find this resource:
72. Valkanova V, Ebmeier KP, Allan CL. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord 2013;150(3):736–744. doi: 10.1016/j.jad.2013.06.004. Review.Find this resource:
73. Decensi A, Omodei U, Robertson C, et al. Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoid-placebo trial in healthy women. Circulation 2002;106(10):1224–1228.Find this resource:
74. Costello EJ, Copeland WE, Shanahan L, Worthman CM, Angold A. C-reactive protein and substance use disorders in adolescence and early adulthood: a prospective analysis. Drug Alcohol Depen 2013;133(2):712–717.Find this resource:
75. Dietrich T, Garcia RI, de Pablo P, Schulze PC, Hoffmann K. The effects of cigarette smoking on C-reactive protein concentrations in men and women and its modification by exogenous oral hormones in women. Eur J Cardiovasc Prev Rehabil 2007;14(5):694–700.Find this resource:
76. Li Y, Rittenhouse-Olson K, Scheider WL, Mu L. Effect of particulate matter air pollution on C-reactive protein: a review of epidemiologic studies. Rev Environ Health 2012;27(2-3):133–149.Find this resource:
77. Lee PC, Talbott EO, Roberts JM, Catov JM, Sharma RK, Ritz B. Particulate air pollution exposure and C-reactive protein during early pregnancy. Epidemiology 2011;22(4):524–531. doi: 10.1097/EDE.0b013e31821c6c58. Erratum in: Epidemiology 2011;22(5):752.Find this resource:
78. Allin KH, Nordestgaard BG. Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Crit Rev Clin Lab Sci 2011;48(4):155–170.Find this resource:
79. Mazhar D, Ngan S. C-reactive protein and colorectal cancer. QJM 2006;99(8):555–559.Find this resource:
80. Williams CB, Yeh ES, Soloff AC. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy. NPJ Breast Cancer 2016;2. pii: 15025.Find this resource:
81. Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancer 2014;6(3):1670–1690.Find this resource:
82. Ittaman SV, VanWormer JJ, Rezkalla SH. The role of aspirin in the prevention of cardiovascular disease. Clin Med Res 2014;12(3-4):147–154.Find this resource:
83. Feldman M, Jialal I, Devaraj S, Cryer B. Effects of low-dose aspirin on serum C-reactive protein and thromboxane B2 concentrations: a placebo-controlled study using a highly sensitive C-reactive protein assay. J Am Coll Cardiol 2001;37(8):2036–2041.Find this resource:
84. Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Brit J Pharmacol 2006;148(3):245–254.Find this resource:
85. Van Arnum P. Tracking growth in biologics: the share of biologic-based drugs in the global pharmaceutical market is on the rise. Pharm Tech 2013;37(2).Find this resource:
86. Catanoso M, Pipitone N, Magnani L, Boiardi L, Salvarani C. New indications for biological therapies. Intern Emerg Med 2011;6(Suppl 1):1–9.Find this resource:
87. Aggarwal BB, Gupta SC, Sung B. Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers. Br J Pharmacol 2013;169(8):1672–1692.Find this resource:
88. Sun J, Zhao Y, Hu J. Curcumin inhibits imiquimod-induced psoriasis-like inflammation by inhibiting IL-1beta and IL-6 production in mice. PLoS One 2013;8(6):e67078.Find this resource:
89. Wang SL, Li Y, Wen Y, et al. Curcumin, a potential inhibitor of up-regulation of TNF-alpha and IL-6 induced by palmitate in 3T3-L1 adipocytes through NF-kappaB and JNK pathway. Biomed Environ Sci 2009;22(1):32–39.Find this resource:
90. Panahi Y, Rahimnia AR, Sharafi M, Alishiri G, Saburi A, Sahebkar A. Curcuminoid treatment for knee osteoarthritis: a randomized double-blind placebo-controlled trial. Phytother Res 2014;28(11):1625–1631.Find this resource:
91. Rahimnia AR, Panahi Y, Alishiri G, Sharafi M, Sahebkar A. Impact of supplementation with curcuminoids on systemic inflammation in patients with knee osteoarthritis: findings from a randomized double-blind placebo-controlled trial. Drug Res (Stuttg) 2015;65(10):521–525.Find this resource:
93. Ganjali S, Sahebkar A, Mahdipour E, et al. Investigation of the effects of curcumin on serum cytokines in obese individuals: a randomized controlled trial. Sci World J 2014;2014:898361.Find this resource:
94. Panahi Y, Saadat A, Beiraghdar F, Sahebkar A. Adjuvant therapy with bioavailability-boosted curcuminoids suppresses systemic inflammation and improves quality of life in patients with solid tumors: a randomized double-blind placebo-controlled trial. Phytother Res 2014;28(10):1461–1467.Find this resource:
95. Klickovic U, Doberer D, Gouya G, et al. Human pharmacokinetics of high dose oral curcumin and its effect on heme oxygenase-1 expression in healthy male subjects. Biomed Res Int 2014;2014:458592.Find this resource:
96. Schiborr C, Kocher A, Behnam D, Jandasek J, Toelstede S, Frank J. The oral bioavailability of curcumin from micronized powder and liquid micelles is significantly increased in healthy humans and differs between sexes. Mol NutrFood Res 2014;58(3):516–527.Find this resource:
97. Ryan JL, Heckler CE, Ling M, et al. Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients. Radiat Res 2013 Jul;180(1):34–43.Find this resource:
98. Chainani-Wu N, Madden E, Lozada-Nur F, Silverman S Jr. High-dose curcuminoids are efficacious in the reduction in symptoms and signs of oral lichen planus. J Am Acad Dermatol 2012 May;66(5):752–760.Find this resource:
99. Chuengsamarn S, Rattanamongkolgul S, Luechapudiporn R, Phisalaphong C, Jirawatnotai S. Curcumin extract for prevention of type 2 diabetes. Diabetes Care 2012;35(11):2121–2127.Find this resource:
100. Wongcharoen W, Jai-Aue S, Phrommintikul A, et al. Effects of curcuminoids on frequency of acute myocardial infarction after coronary artery bypass grafting. Am J Cardiol 2012;110(1):40–44.Find this resource:
101. Gupta SC, Tyagi AK, Deshmukh-Taskar P, Hinojosa M, Prasad S, Aggarwal BB. Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. Arch Biochem Biophys 2014;559:91–99.Find this resource:
102. Ebrahimpour Koujan S, Gargari BP, Mobasseri M, Valizadeh H, Asghari-Jafarabadi M. Effects of Silybum marianum (L.) Gaertn. (silymarin) extract supplementation on antioxidant status and hs-CRP in patients with type 2 diabetes mellitus: a randomized, triple-blind, placebo-controlled clinical trial. Phytomedicine 2015;22(2):290–296.Find this resource:
103. Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989;9(1):105–113. PubMed PMID: 2671116.Find this resource:
104. Fried MW, Navarro VJ, Afdhal N, et al; Silymarin in NASH and C Hepatitis (SyNCH) Study Group. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. JAMA 2012;308(3):274–282.Find this resource:
105. Li M, Liu JT, Pang XM, Han CJ, Mao JJ. Epigallocatechin-3-gallate inhibits angiotensin II and interleukin-6-induced C-reactive protein production in macrophages. Pharmacol Rep 2012;64(4):912–918.Find this resource:
106. Kou W, Sun R, Wei P, et al. Andrographolide suppresses IL-6/Stat3 signaling in peripheral blood mononuclear cells from patients with chronic rhinosinusitis with nasal polyps. Inflammation 2014;37(5):1738–1743.Find this resource:
107. Chun JY, Tummala R, Nadiminty N, et al. Andrographolide, an herbal medicine, inhibits interleukin-6 expression and suppresses prostate cancer cell growth. Genes Cancer 2010;1(8):868–876.Find this resource:
108. Sandborn WJ, Targan SR, Byers VS, et al. Andrographis paniculata extract (HMPL-004) for active ulcerative colitis. Am J Gastroenterol 2013;108(1):90–98.Find this resource:
109. Saxena RC, Singh R, Kumar P, et al. A randomized double blind placebo controlled clinical evaluation of extract of Andrographis paniculata (KalmCold) in patients with uncomplicated upper respiratory tract infection. Phytomedicine 2010;17(3-4):178–185.Find this resource:
110. Chen W, Padilla MT, Xu X, et al. Quercetin inhibits multiple pathways involved in interleukin 6 secretion from human lung fibroblasts and activity in bronchial epithelial cell transformation induced by benzo[a]pyrene diol epoxide. Mol Carcinog 2016;55(11):1858–1866.Find this resource:
111. Kim BH, Lee IJ, Lee HY, et al. Quercetin 3-O-beta-(2’’-galloyl)-glucopyranoside inhibits endotoxin LPS-induced IL-6 expression and NF-kappa B activation in macrophages. Cytokine 2007;39(3):207–215.Find this resource:
112. Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem 2009;1(7):1333–1349.Find this resource:
113. Naftali T, Bar-Lev Schleider L, Dotan I, Lansky EP, Sklerovsky Benjaminov F, Konikoff FM. Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clin Gastroenterol Hepatol 2013;11(10):1276–1280.e1.Find this resource:
114. Kasapis C, Thompson PD. The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review. J Am Coll Cardiol 2005;45(10):1563–1569.Find this resource:
115. Ryan AS, Ge S, Blumenthal JB, Serra MC, Prior SJ, Goldberg AP. Aerobic exercise and weight loss reduce vascular markers of inflammation and improve insulin sensitivity in obese women. J Am Geriatr Soc 2014;62(4):607–614.Find this resource:
116. Kasapis C, Thompson PD. The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review. J Am Coll Cardiol 2005;45(10):1563–1569.Find this resource:
117. Arikawa AY, Thomas W, Schmitz KH, Kurzer MS. Sixteen weeks of exercise reduces C-reactive protein levels in young women. Med Sci Sports Exerc 2011;43(6):1002–1009.Find this resource:
118. Beavers KM, Brinkley TE, Nicklas BJ. Effect of exercise training on chronic inflammation. Clin Chim Acta 2010;411:785–793.Find this resource:
120. Taylor C, Rogers G, Goodman C. Hematologic, iron-related, and acute-phase protein responses to sustained strenuous exercise. J Appl Physiol 1987;62:464–469.Find this resource:
121. Rodríguez-Hernández H, Simental-Mendía LE, Rodríguez-Ramírez G, Reyes-Romero MA. Obesity and inflammation: epidemiology, risk factors, and markers of inflammation. Int J Endocrinol 2013;2013:Article ID 678159.Find this resource:
122. Forsythe LK, Wallace JM, Livingstone MB. Obesity and inflammation: the effects of weight loss. Nutr Res Rev 2008;21(2):117–133.Find this resource:
123. Deng T, Lyon CJ, Bergin S, Caligiuri MA, Hsueh WA. Obesity, inflammation, and cancer. Annu Rev Pathol 2016;11:1–644.Find this resource:
124. Slavin JL. Dietary fiber and body weight. Nutrition 2005;21(3):411–418. Review.Find this resource:
125. Champagne CM, Broyles ST, Moran LD, et al. Dietary intakes associated with successful weight loss and maintenance during the Weight Loss Maintenance Trial. J Am Diet Assoc 2011;111(12):1826–1835.Find this resource:
126. Jiao J, Xu JY, Zhang W, Han S, Qin LQ. Effect of dietary fiber on circulating C-reactive protein in overweight and obese adults: a meta-analysis of randomized controlled trials. Int J Food Sci Nutr 2015;66(1):114–119.Find this resource:
127. Ning H, Van Horn L, Shay CM, Lloyd-Jones DM. Associations of dietary fiber intake with long-term predicted cardiovascular disease risk and C-reactive protein levels (from the National Health and Nutrition Examination Survey Data [2005–2010]). Am J Cardiol 2014;113(2):287–291.Find this resource:
128. Ma Y, Griffith JA, Chasan-Taber L, et al. Association between dietary fiber and serum C-reactive protein. Am J Clin Nutr 2006;83(4):760–766.Find this resource:
129. King DE, Mainous AG, Egan BM, Woolson RF, Geesey ME. Effect of psyllium fiber supplementation on C-reactive protein: the Trial to Reduce Inflammatory Markers (TRIM). Ann Fam Med 2008;6(2):100–106.Find this resource:
130. North CJ, Venter CS, Jerling JC. The effects of dietary fibre on C-reactive protein, an inflammation marker predicting cardiovascular disease. Eur J Clin Nutr 2009;63(8):921–933. doi: 10.1038/ejcn.2009.8. Review.Find this resource:
131. Zampelas A, Panagiotakos DB, Pitsavos C, et al. Fish consumption among healthy adults is associated with decreased levels of inflammatory markers related to cardiovascular disease: the ATTICA study. J Am Coll Cardiol 2005;46(1):120–124.Find this resource:
132. Pot GK, Geelen A, Majsak-Newman G, et al. Increased consumption of fatty and lean fish reduces serum C-reactive protein concentrations but not inflammation markers in feces and in colonic biopsies. J Nutr 2010;140(2):371–376.Find this resource:
133. Bowden RG, Wilson RL, Deike E, Gentile M. Fish oil supplementation lowers C-reactive protein levels independent of triglyceride reduction in patients with end-stage renal disease. Nutr Clin Pract 2009;24(4):508–512.Find this resource:
134. Kremer JM, Jubiz W, Michalek A, et al. Fish-oil fatty acid supplementation in active rheumatoid arthritis: a double-blinded, controlled, crossover study. Ann Intern Med 1987;106(4):497–503.Find this resource:
135. Proudman SM, James MJ, Spargo LD, et al. Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use. Ann Rheum Dis 2015;74(1):89–95.Find this resource:
136. Roseman C, Truedsson L, Kapetanovic MC. The effect of smoking and alcohol consumption on markers of systemic inflammation, immunoglobulin levels and immune response following pneumococcal vaccination in patients with arthritis. Arthritis Res Ther 2012;14(4):R170.Find this resource:
137. Sacanella E, Vázquez-Agell M, Mena MP, et al. Down-regulation of adhesion molecules and other inflammatory biomarkers after moderate wine consumption in healthy women: a randomized trial. Am J Clin Nutr 2007;86(5):1463–1469.Find this resource:
138. Retterstol L, Berge KE, Braaten Ø, Eikvar L, Pedersen TR, Sandvik L. A daily glass of red wine: does it affect markers of inflammation? Alcohol Alcohol 2005;40(2):102–105.Find this resource:
139. McDonald JA, Goyal A, Terry MB. Alcohol intake and breast cancer risk: weighing the overall evidence. Curr Breast Cancer Rep 2013;5(3):10.1007/s12609-013-0114-z.Find this resource:
140. Vijayaraghava A, Doreswamy V, Narasipur OS, Kunnavil R, Srinivasamurthy N. Effect of yoga practice on levels of inflammatory markers after moderate and strenuous exercise. J Clin Diagn Res 2015;9(6):CC08–CC12.Find this resource:
141. Kiecolt-Glaser JK, Bennett JM, Andridge R, et al. Yoga’s impact on inflammation, mood, and fatigue in breast cancer survivors: a randomized controlled trial. J Clin Oncol 2014;32(10):1040–1049.Find this resource:
142. Twal WO, Wahlquist AE, Balasubramanian S. Yogic breathing when compared to attention control reduces the levels of pro-inflammatory biomarkers in saliva: a pilot randomized controlled trial. BMC Complement Altern Med 2016;16:294.Find this resource:
143. Creswell JD, et al. Alterations in resting-state functional connectivity link mindfulness meditation with reduced interleukin-6: a randomized controlled trial. Biol Psychiat 2016 July;80(1):53–61.Find this resource:
144. Black DS, Slavich GM. Mindfulness meditation and the immune system: a systematic review of randomized controlled trials. Ann N Y Acad Sci 2016;1373(1):13–24.Find this resource:
145. Rosenkranz MA, Davidson RJ, Maccoon DG, Sheridan JF, Kalin NH, Lutz A. A comparison of mindfulness-based stress reduction and an active control in modulation of neurogenic inflammation. Brain Behav Immun 2013;27(1):174–184.Find this resource:
146. Crane JD, Ogborn DI, Cupido C, et al. Massage therapy attenuates inflammatory signaling after exercise-induced muscle damage. Sci Transl Med 2012;4(119):119ra13.Find this resource:
147. Zijlstra FJ, van den Berg-de Lange I, Huygen FJ, Klein J. Anti-inflammatory actions of acupuncture. Mediators Inflamm 2003;12(2):59–69. Review.Find this resource:
148. Kavoussi B, Ross BE. The neuroimmune basis of anti-inflammatory acupuncture. Integr Cancer Ther 2007;6(3):251–257. Review.Find this resource:
149. McDonald JL, Cripps AW, Smith PK, Smith CA, Xue CC, Golianu B. The anti-inflammatory effects of acupuncture and their relevance to allergic rhinitis: a narrative review and proposed model. Evid Based Complement Alternat Med 2013;2013:591796.Find this resource:
150. Vickers AJ, Cronin AM, Maschino AC, et al; Acupuncture Trialists’ Collaboration. Acupuncture for chronic pain: individual patient data meta-analysis. Arch Intern Med 2012;172(19):1444–1453.Find this resource:
151. Fagundes CP, Bennett JM, Derry HM, Kiecolt-Glaser JK. Relationships and inflammation across the lifespan: social developmental pathways to disease. Social and Personality Psychology Compass 2011;5(11):891–903.Find this resource: