Acute Inflammation (Good) vs. Chronic Inflammation (Bad)

Click here for a mobile-friendly version.

Inflammation may have started as the solution—for example, as a way to rid the body of a dangerous invader—but if it doesn't turn off when it should, it instead can become the problem. 

To protect itself and try to remove the injurious stimuli, the body triggers the inflammation, an elaborate response involving the vascular system, the immune system, and various cells within the injured tissue. 

The classic signs of inflammation — swelling, pain, redness and loss of function — usually appear after an injury. 

The body's immune response may keep inflammation going, long after the threat has cleared. Acute inflammation has now transitioned to chronic inflammation.

Chronic inflammation plays a central role in some of the most challenging diseases of our time, including rheumatoid arthritis, cancer, heart disease, diabetes, asthma, and even Alzheimer’s.^[13-15,27]

Oxidative Stress

At the center of inflammation is the concept of oxidative stress, which is like a biological type of "rusting" of our organs and tissues.  Oxidation is a normal part of everyday living, but oxidation in overdrive can become a problem.

This can happen both on the outside and the inside:

• Outside
• Can cause wrinkles and premature aging
• Inside
• Can stiffen our blood vessels, damage cell membranes, and essentially wreak havoc on our precious interior designs

Video 1.  Foods That Cause Inflammation (YouTube link)

Acute Inflammation

In acute inflammatory response, a number of secreted molecules include: 

• C-reactive protein (CRP)
• CRP is produced by the liver only during episodes of acute inflammation. It is highly correlated with obesity, cardiovascular diseases, diabetes, and cancers.
• IL-1β
• IL-6
• IL-6 is an important mediator of fever and of the acute phase response.
• TNF-α

have been validated.  However, in age-related chronic inflammation, no standard cytokine signature exists.^[16,17]

There is abundant evidence that certain pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α are involved in the process of pathological pain.

Canonical acute inflammation proteins (CRP, IL-6, etc.) have also been associated with immunosenescence in previous studies.  

Immunosenescence is the gradual deterioration of the immune system, brought on by natural age advancement. Generally, it is believed that the adaptive immune system is affected more than the innate immune system. Immunosenescence involves both the host's capacity to respond to infections and the development of long-term immune memory.

How Chronic Inflammation Develop?

Inflammatory components of the immune system are often chronically elevated in aged individuals.  

Contrary to the acute response, which is typically triggered by infection, chronic inflammation is thought to be triggered by physical, chemical or metabolic noxious stimuli (“sterile” agents) such as those released by damaged cells and environmental insults, generally termed “damage-associated molecular patterns” (DAMPs). This type of inflammation is associated with aging and characterized by being low-grade and persistent, ultimately leading to collateral damage to tissues and organs.^[12,13]

Cytokines have an important function in the body, activating the immune system to fight infection. But because they work by an inflammatory process, when they’re overproduced they put the body into a state of chronic inflammation, which causes cells to age faster.  Chronic inflammation can develop in several ways:

1. Threat remains
• The immune system is pretty good at eliminating invaders, but sometimes pathogens resist even our best defenses and hide out in tissues, provoking the inflammatory response again and again.
2. Autoimmune disorder
• The immune system goes into "threat mode" when no true threat exists.  It reacts against the joints, intestines, or other organs and tissues as if they were dangerous. As the inflammatory response continues, it damages the body instead of healing it.
3. Unhealthful lifestyle
• Smoking, failing to exercise regularly, or eating a diet high in refined carbohydrates can contribute to chronic inflammation. For example, 
• Those on a “high-salt diet displayed a markedly higher number of monocytes,” which are a type of immune cell you often see increased in settings of chronic inflammation and autoimmune disorders.^[9]

Symptoms of Chronic Inflammation

The signs of chronic inflammation are not as obvious as those of acute inflammation. No sharp twinge of pain as when you cut yourself, no swelling or redness will you see to alert you to a problem. 

Chronic inflammation can be widespread or more localized to specific areas of the body. Therefore the symptoms can vary considerably, such as:

• Fatigue and lack of energy
• Depression, anxiety
• Muscle aches and joint pain
• Constipation, diarrhea, and other gastrointestinal complaints
• Changes in weight or appetite
• Headaches
• Brain fog (a "fuzzy" mental state)

Chronic inflammation and Diseases

Your joints

When you suffer a joint injury — maybe a banged-up knee or a twisted ankle — a little inflammation is part of the healing process. Puffy, red, tender joints may indicate that your immune system is working to remove damage and promote the growth of new tissue, a healthy kind of inflammation. But sometimes the immune system launches unhealthy, chronic inflammation in the joints, for no apparent reason. This leads to pain, stiffness, and joint damage known as inflammatory arthritis.

Your Heart

The buildup of inflammation — not necessarily cholesterol — is what can lead to a heart attack.^[24]

• Inflammation in the artery wall is the real cause of heart disease‏
• Without inflammation, cholesterol would move freely throughout the body as nature intended. It is inflammation that causes cholesterol to become trapped.

The actual sequence of actions that takes place beginning with inflammation and ending in an actual heart attack is complex (read [6] for details), involving changes to the coronary artery and blood vessels that nourish the heart, but the outcome is the same: an increased risk for a life-threatening cardiovascular event.

Figure 1. Overview of cellular and molecular processes that govern inflammation and its resolution (Source: [24])

Resolution of Inflammation

To prevent progression from acute inflammation to cchronic inflammation, the inflammatory response must be suppressed to prevent additional tissue damage. Inflammation resolution is a well-managed process :

• Involves the spatially- and temporally-controlled production of mediators
• During which chemokine gradients are diluted over time. 
• Circulating white blood cells eventually no longer sense these gradients and are not recruited to sites of injury.
• Dysregulation of this process 
• Can lead to uncontrolled chronic inflammation

Inflammation resolution processes that rectify tissue homeostasis include reduction or cessation of tissue infiltration by neutrophils and apoptosis of spent neutrophils, counter-regulation of chemokines and cytokines, macrophage transformation from classically to alternatively activated cells, and initiation of healing.

Conclusions

Inflammation is traditionally defined by its cardinal signs—redness, swelling, heat, and pain—which are induced by infection or tissue injury. But a growing body of evidence shows that inflammatory cells and mediators are also important for homeostatic functions, such as metabolism, tissue remodeling, and interorgan cross-talk.^[26]

Inflammatory cells and molecules play important roles in acute responses to infection as well as to tissue perturbations. Thus, inflammation exists on a spectrum that can be tuned up or down, depending on the context.

Inflammatory responses exhibit substantial variability among individuals. Our growing understanding of the ubiquitous nature of inflammation and its diverse roles will benefit a wide range of efforts to treat, prevent, and ameliorate disease.

References

1. The impact of nutrition on COVID-19 susceptibility and long-term consequences
2. Anti-inflammatory effect and mechanism of proanthocyanidins from grape seeds.
3. Feeling Beat Up After Workouts? 5 Superfoods May Help
4. Researchers identify key protein involved in triggering inflammation
5. An Inflammatory Clock Predicts Multi-morbidity, Immunosenescence and Cardiovascular Aging in Humans
6. Inflammatory responses and inflammation-associated diseases in organs (Good)
7. How diet influences gut bacteria and inflammation
8. Long-term dietary patterns are associated with pro-inflammatory and anti-inflammatory features of the gut microbiome
9. Sodium and Autoimmune Disease: Rubbing Salt in the Wound?
10. Advanced Glycation End-Products: A Biological Consequence of Lifestyle Contributing to Cancer Disparity
11. Immunity, Inflammation, and Cancer (good)
12. Goldberg, E.L., and Dixit, V.D. (2015). Drivers of age-related inflammation and strategies for healthspan extension. Immunological reviews 265, 63-74.
13. Kotas, M.E., and Medzhitov, R. (2015). Homeostasis, inflammation, and disease susceptibility. Cell 160, 816-827.
    
14. Crusz, S.M., and Balkwill, F.R. (2015). Inflammation and cancer: advances and new agents. Nature reviews Clinical oncology 12, 584-596.
15. Liu, C.H., Abrams, N.D., Carrick, D.M., Chander, P., Dwyer, J., Hamlet, M.R.J., Macchiarini, F., PrabhuDas, M., Shen, G.L., Tandon, P., et al. (2017). Biomarkers of chronic inflammation in disease development and prevention: challenges and opportunities. Nature immunology 18, 1175-1180.
16. Franceschi, C., Garagnani, P., Vitale, G., Capri, M., and Salvioli, S. (2017). Inflammaging and ’Garb-aging’. Trends in endocrinology and metabolism: TEM 28, 199–212.
17. Morrisette-Thomas, V., Cohen, A.A., Fulop, T., Riesco, E., Legault, V., Li, Q., Milot, E., Dusseault-Belanger, F., and Ferrucci, L. (2014). Inflamm-aging does not simply reflect increases in pro-inflammatory markers. Mechanisms of ageing and development 139, 49–57.
18. Oregon University Linus Pauling Institute
19. Epel, E.S., B. McEwen, T. Seeman, et al. Stress and body shape: Stress-induced cortisol secretion is consistently greater among women with central fat. Psychosomatic Medicine 2000:62(5):623-32.
20. The End of Illness by David B. Agus, MD
21. Common Drug Has The Potential To Slow Aging, Boost Cancer
22. Bowel Disease Increases Risk for Stroke and Heart Attack
23. WORLD RENOWNED HEART SURGEON SPEAKS OUT ON WHAT REALLY CAUSES HEART DISEASE
24. The Truth about Cholesterol (Travel to Health)
25. Resolution of Inflammation: What Controls Its Onset?
26. Inflammation: An expanding view
27. Common Pathophysiology in Cancer, Atrial Fibrillation, Atherosclerosis, and Thrombosis: JACC: CardioOncology State-of-the-Art Review

The Truth about Cholesterol

Is cholesterol really the bad guy? The answer is yes-and-no: it depends. In this article, we will discuss the myths and facts of cholesterol.

The Cholesterol Myth: What Really Clogs Our Arteries (YouTube link)

Is Cholesterol Really the Bad Guy?

In [1], Dr. Dwight Lundell said:

As a heart surgeon with 25 years experience, having performed over 5,000 open-heart surgeries,today is my day to right the wrong with medical and scientific fact.

In a nutshell, here are his statements:

What Was Wrong?	Heart disease resulted from the simple fact of elevated blood cholesterol. The only accepted therapy was prescribing medications to lower cholesterol (hint: statins) and a diet that severely restricted fat intake.
What Is the Answer?	Inflammation in the artery wall is the real cause of heart disease.[1,16,22,25] Without inflammation being present in the body, there is no way that cholesterol would accumulate in the wall of the blood vessel and cause heart disease and strokes.

If cholesterol alone were the bad guy, then the pill named evacetrapib would be the miracle cures for most heart diseases because evacetrapib can:

• Substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity

But, based on a research, it concludes that:^[23]

Treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease and the trial was terminated early because of a lack of efficacy.

Figure 1.  Healthy Heart for all

What is Cholesterol?

Cholesterol^[3,6] is a lipidic (or fatty), waxy steroid found in the cell membranes and transported in the blood plasma. Here are the facts of cholesterol:

• Body needs cholesterol
• For its structural role in the cell membrane—to maintain membrane permeability and fluidity
• As a precursor for the biosynthesis of steroid hormones, bile acids, vitamin D, and the adrenal gland hormones cortisol and aldosterone^[4]
• No cholesterol, no sex
• As a precursor for synthesizing the sex hormones progesterone, estrogens, and testosterone and their derivatives.^[4]
• For muscle mass buildup
• The research at TAMU revealed that following relatively vigorous workouts, individuals who had the most muscle mass gain also had the highest LDL cholesterol levels.^[20]
• For skin protection
• In the skin, cholesterol is secreted by glands just below the surface to protect against dehydration and the wear and tear of sun, wind, and water.^[3]
• For healing wounds and protecting against infections.^[5]
• Almost every cell in the body manufactures cholesterol
• In vertebrates, the liver typically produces greater amounts than other cells.
• Even you eat foods with little cholesterol ingredients, your body will still manufacture at least 1,000 mg of pure cholesterol each day.

Figure 2. Main target organs of oxysterols during ageing and aged-related diseases

• Cholesterol may act as an antioxidant^[7]
• It can stand in to perform an antioxidant function when certain vitamins and minerals are in low supply.
• However, cholesterol is damaged in the process, and oxidized cholesterol is bad for the body.^[29]
• The accumulation of oxysterols can be cytotoxic, mutagenic, atherogenic, and possibly carcinogenic—in other words, toxic to cells, toxic to DNA, and contributing to heart disease and maybe cancer.
• That's why getting antioxidants in a steady supply throughout the day is important. Let your vitamins and minerals protect you from free radicals so they can allow your cholesterol to play all of its other life-saving roles.

Video 1.  Oxidized Cholesterol as a Cause of Alzheimer's Disease (YouTube link)

What is Inflammation?

By itself, cholesterol does not cause heart disease and stroke. Atherosclerosis is an inflammatory disease. It's what inflammation does to cholesterol that causes arterial plaques.^[11]

Inflammation is simply our body’s natural defense to a foreign intruder (i.e., bacteria, toxin or virus).^[1] The cycle of inflammation is perfect in how it protects our body from these bacterial and viral intruders. However, if we chronically expose the body to injury by toxins or western diets the human body was never designed to process, a condition occurs called chronic inflammation.

Connection between Inflammation and Plasma Fibrinogen Level

There's a strong and well-established connection between inflammation and plasma fibrinogen level.

Here's a breakdown of their relationship:^[35-39]

Inflammation: When your body encounters a threat, like an infection or injury, the immune system triggers inflammation. This process involves releasing various chemicals, including cytokines, that signal the body to heal and defend itself.
Fibrinogen: This is a plasma protein essential for blood clotting. It helps form a fibrin mesh that traps blood cells and platelets, stopping bleeding.
The Link: During inflammation, cytokines also stimulate the liver to produce more fibrinogen. This increased production elevates plasma fibrinogen levels, contributing to several outcomes:

• Acute Phase Response: This refers to the body's overall response to inflammation, and elevated fibrinogen is a hallmark feature.
• Blood Clotting: Higher fibrinogen levels increase the blood's clotting potential, potentially leading to risks like thrombosis (blood clot formation) if not regulated properly.
• Chronic Inflammation: In conditions with long-term inflammation, like autoimmune diseases or rheumatoid arthritis, chronically elevated fibrinogen levels are often observed. This might contribute to tissue damage and disease progression.

Important Points:

• Not everyone with elevated fibrinogen levels will experience complications. Other factors like genetics, lifestyle, and underlying health conditions play a role.
• Treatment for high fibrinogen typically focuses on addressing the underlying inflammatory cause, not directly lowering fibrinogen itself.
• Consulting a healthcare professional is crucial if you have concerns about your fibrinogen levels or inflammatory status.

Video 2.  High Cholesterol is Healthy! [with David Diamond, PhD] (YouTube link)

Causal Effect of Blood Clotting on Heart Attack and Stroke

Blood clotting plays a crucial role in both heart attacks and strokes, but the specific causal links differ slightly.

Key Points:

• Blood clots themselves don't directly cause heart attacks or strokes. However, they worsen pre-existing conditions and trigger the events.
• Different types of arteries and specific causes of clot formation contribute to each scenario.
• Prevention focuses on managing risk factors for plaque buildup, blood clotting, and heart/brain health.

Summary

In this article, we have shown you that cholesterol is an essential nutrient. Driving your cholesterol levels down too far can cause serious health problems.

In a first study that explores the independent risk factors of long-term all-cause mortality in coronary artery disease patients with well-controlled LDL-C levels, authors have found that:^[32]

The relative risk was highest for severe malnutrition. Considering the prevalence of identified risk factors, the highest population attributable risk was found for mild malnutrition, followed by chronic kidney disease, moderate malnutrition, age ≥75 years, congestive heart failure, severe malnutrition and atrial fibrillation.

To recap, atherosclerosis is an inflammatory disease. Inflammation in general are almost never the presence of too much cholesterol alone—rather they are too little of many other compounds: antioxidants, vitamins, minerals, omega-3 fatty acids, etc.

Without inflammation, cholesterol would move freely throughout the body as nature intended. It is inflammation that causes cholesterol to become trapped. As noted in previous section, chronic inflammation is harmful while acute inflammation is beneficial. To become healthy is to avoid chronic inflammation. As Dr. Dwight Lundell pointed out, the culprits of chronic inflammation is our western diets:^[1,8]

What are the biggest culprits of chronic inflammation? Quite simply, they are the overload of simple, highly processed carbohydrates (sugar, flour and all the products made from them) and the excess consumption of omega-6 vegetable oils like soybean, corn and sunflower that are found in many processed foods.

Without much ado, I would refer you to watch [1] for the causation of heart diseases:

Western diets -> High blood sugar -> Glycation -> Chronic inflammation -> Heart diseases

Remember this: Avoiding heart disease begins and ends with following a healthy lifestyle, not with pharmaceuticals. Poisoning your cells' ability to make cholesterol isn't the best way to avoid heart disease.  

Warning: If you have concerns about your cholesterol levels, always consult a qualified healthcare professional for personalized advice based on your individual risk factors and medical history.

Photo Credit

• 2healthcare.net

References

1. The Truth About Heart Disease & Cholesterol — Dwight Lundell
2. The Healthy Home by Dave Wentz and Dr. Myron Wentz
• Every patient is different, and every case of heart disease involves a multitude of factors, from diet to activity level to lifestyle, as well as the genetic diversity of the human race.
3. U. Erasmus, Fats That Heal, Fats That Kill (Burnaby BC, Canada: Alive Books, 1993).
4. Hanukoglu I (Dec 1992). "Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis.". J Steroid Biochem Mol Biol 43 (8): 779–804.
5. U. Ravnskov, "High Cholesterol May Protect Against Infections and Atherosclerosis," QJM Internaltional Journal of Medicine 96 (2003): 927-34.
6. Cholesterol (Wikipedia)
7. Smith LL (1991). "Another cholesterol hypothesis: cholesterol as antioxidant". Free Radic. Biol. Med. 11 (1): 47–61.
8. Western Diets and Western Diseases (Travel and Health)
9. Omega-3 Fatty Acids (Travel and Health)
10. 10 Things You Didn't Know About Cholesterol (Everyday Health)
11. Check out "Pathology of Atherosclerotic Plaque" of this article
12. David Seaman: Inflammation From Our Diet Is Killing Us Slowly (a must-watch video)
13. Statin Drugs and Diabetes
• Statin drugs can increase women's risk of diabetes by 48%
14. The Little-Known Vitamin Essential to Your Health
• Vitamin K2 deficiency can cause calcium-buildup, which can increase the risk of calcification of the arteries and hence the heart disease.
15. High Cholesterol Tied to Prostate Cancer's Return in Study
• But expert doesn't recommend taking statins to prevent recurrence
16. The Real Cause of Heart Disease
17. The Overlooked Health Risks of Very Low Cholesterol
18. New Scientific Analysis Confirms Saturated Fats Have No Link to Heart Disease
19. The incredible cholesterol-lowering benefits of the Avocado
20. Bad Cholesterol Not As Bad As People Think, Study Shows (TAMU)
21. Flaxseed dietary fibers lower cholesterol and increase fecal fat excretion, but magnitude of effect depend on food type
• Research has shown that consuming flaxseed daily can help to reduce bad cholesterol.
22. Deep Vein Thrombosis (DVT)
• Anything that damages the inner lining of a vein may cause DVT -- surgery, an injury, or your immune system. 
• People who have certain genetic disorders or more estrogen in their system are more likely to have blood clots, too.
• Higher levels of estrogen during pregnancy may make blood clot more easily
23. Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease
24. Heart attack symptoms: Know what's a medical emergency
25. Novartis Drug Becomes First To Prevent Heart Attacks And Strokes By Targeting Inflammation
26. The Cholesterol Myth Has Been Busted — Yet Again
27. Rethinking good cholesterol — A high HDL cholesterol level may not be as beneficial as once believed.
28. The best food for high cholesterol (Dr Michael Greger)
29. Oxidized Cholesterol as a Cause of Alzheimer’s Disease
30. Low Fat Diet Associated With Reduced Testosterone Levels
31. Chest Pain: 3 Signs It’s Not a Heart Attack and Possible Causes
32. Wang B, Liu J, Chen S, Ying M, Chen G, Liu L, et al. Malnutrition affects cholesterol paradox in coronary artery disease: a 41,229 chinese cohort study. Lipids Health Dis. (2021) 20:36.
33. Can High Cholesterol Cause Headaches?
34. Is It Better to Drink Little Alcohol Than None? Do Any Benefits of Alcohol Outweigh the Risks?
35. Acute phase reaction and acute phase proteins
36. C-Reactive Protein: A Simple Test to Help Predict Risk of Heart Attack and Stroke
37. What are blood clots and what causes them?
38. Association Between γ′ Fibrinogen Levels and Inflammation
39. Fibrinogen, Fibrin, and Fibrin Degradation Products in COVID-19
40. Weighing the Risks and Benefits of Statins (Michael Greger, M.D.)