Cytokines and Inflammation: Balance Required

Inflammation is bad, right? Chronic inflammation has been implicated in cardiovascular disease, type 2 diabetes, non-alcoholic fatty liver disease, cancer, autoimmune diseases, Alzheimer’s disease, other neurodegenerative disorders and more. Ad campaigns for new anti-inflammatory drugs are everywhere, and the best-selling over the counter pain relievers, taken by millions of people, work by suppressing inflammation. It is easy to get the impression that inflammation is always detrimental to health. But, without inflammation, all injuries would be permanent and our defenses against bacterial and viral invaders would be feeble. The inflammatory process is vital to life, the necessary first step in healing and in the body’s defense against infection.  But there is a dark side to this finely tuned system.  Inflammation can become chronic, outlasting the need for defense and repair, and damaging normal tissues in the process.

How inflammation works

Inflammation begins the when cells send out signals that they have been injured, by thermal or physical forces, or attacked, by organisms like bacteria or viruses. The language of this cellular communication is chemical, involving messenger molecules called cytokines (cyto meaning cell and kine, from kinos, meaning movement).  Cytokines attract of white blood cells to the area of injury, and they open pores in nearby tiny blood vessels to let in this defensive army, along with variety of specialized proteins that begin the job of healing.  Inflammation is the word used for the changes that occur in tissues as a result of the orderly events that ensue. With successful healing, signs of inflammation subside, and cellular cytokine production returns to the baseline level necessary for routine cellular maintenance and regeneration.

The normal course of healing inflammation

The cardinal signs of inflammation are redness, heat, swelling and pain. Redness, heat and swelling come from the increase in blood flow and permeability of the blood vessels. Pain is the result of cytokine stimulation of tiny nerve endings, and serves the purpose of limiting movement to limit further damage.  Some cytokine signals reach the temperature control centers in the brain, raising the body temperature to levels invading organisms tolerate poorly. Specialized immune cells immobilize and kill viruses and bacteria and cleanup cells called macrophages clear the debris. Gradually, dead and dying cells are walled off and disposed of. Rebuilding begins, taking advantage of scaffolding produced by the proteins which have leaked from the blood and caused clots to from. You see this process every time scab forms on a cut and later shrinks and peels away to reveal new skin cells beneath.

Maladaptive inflammation

But sometimes the inflammatory system does not gear back down, resulting in tissue damage rather than repair. This control failure may be rapid and catastrophic, the so-called cytokine storm, a term which has become familiar during the 2020 SARS-COV19 pandemic. It describes the damaging effects of an overreaction of the inflammatory response triggered by the immune system during infection or severe trauma. Oncoming cytokine storm cannot be predicted based on routine clinical parameters or tests, but researchers are beginning to tease out more sophisticated chemical markers of inflammation which correlate with more severe disease.

Maladaptive inflammation can also be slow and chronic, with progressive tissue damage like that which occurs in rheumatoid arthritis. The causes of such chronic inflammatory responses are legion and many don’t have obvious relationships to the normal inflammatory pathways. They include obesity, inactivity, toxic chemicals in food and the environment (xenobiotics), poor sleep, chronic infections and antibiotics that alter the normal bowel bacterial populations. Chronic inflammation is also a result of autoimmune responses to the body’s own tissues – cross reactions between immune responses to external agents and to the body’s cells, particularly in skin or joints and other organs like the thyroid gland. No one understands exactly why these self attacks begin to occur but autoimmunity is on the rise in all age groups.

Intertwined systems

The wide ranging influences on the inflammatory system reveals the deep connections between the body’s different physiologic systems. Disruption in one system influences production of chemical signalers in another. For instance, stress and lack of sleep suppress normal defenses against infections. External factors as simple as poor mechanical care of teeth allow chronic gum infections to take hold. Smoking and air pollution irritate the lungs. Lack of exercise changes the way blood flows though arteries, setting them up for damage and chronic inflammatory repair processes. And chronic use of anti-inflammatory drugs for aches and pains alters the finely tuned balance of cytokine signaling throughout the body. 

As we age, chronic inflammatory markers – measurements of some select cytokines like C-reactive protein – tend to rise. Attention to diet, exercise, sleep, dental care and stress management are within your control and help suppress inflammatory marker levels. Removal of allergens and irritating chemical triggers like smoke from the environment helps, as does attention to areas of the body that are sites of chronic infection, like teeth and skin.  

Pharmaceutical interventions are common ways of suppressing chronic inflammation. The NSAIDS, non-steroidal anti-inflammatory drugs like Advil, block cytokines called prostaglandins. Most recently, drugs-called biologicals target individual cytokines by blocking them with antibodies. The new biological drugs provide significant relief to people who suffer from autoimmune problems, but they can also impair the primary functions of defense and repair. Caution is required and risk-benefit calculations are necessary, because opportunistic infections – ones that the body normally handles well – can take hold and thrive. The body’s innate cancer surveillance system, which finds abnormal cells and induces their death before they become malignant, can also become less functional.  

Maintaining the Balance 

Cytokines and the inflammation they cause are part of an enormously complex, finely balanced cellular maintenance and body defense system. Small disruptions in the balance over time, such as happens with chronic use of anti-inflammatory drugs for treatment of pain, or chronic stimulation from infection, can show up in odd and seemingly unrelated ways, like an increased rate of heart attacks and strokes in chronic NSAID users and development of liver cancer in hepatitis sufferers. In an imperfect world, perfect balance is hard to maintain, but the inflammatory response system is far more often good than bad.    

Blood Clotting…and Not Clotting

    Over a gallon of blood circles your body every 45 seconds, under pressure, in a network of arteries, veins and capillaries.  Any leaks in the system must be plugged and repaired. Some ruptures are emergencies requiring outside help, but most are fixed handily by a well calibrated system of physical and chemical reactions in your body.  You watch this process every time you cut yourself shaving or slicing tomatoes, but it also happens microscopically, all over your body, when blood vessels are damaged internally by trauma or infection or chronic degenerative changes in the walls of arteries.  

How clotting happens 

Hemostasis, the first step in controlling bleeding, involves mechanical measures like pressure, cautery or stitches to stop blood flow from damaged blood vessels. Hemostasis alone is ineffective and must to be accompanied by blood clotting, a process triggered by blood platelets, which are tiny little disc shaped cell fragments that accumulate at the site of blood vessel injury. About a trillion platelets circulate in the blood, speeding by over 10,000 square feet endothelial cells that line the inside walls of blood vessels. When damage exposes collagen and other proteins in the endothelial cells and surrounding tissues, platelets gather to plug the defect, while secreting chemicals that draw white blood cells to the scene. An orderly sequence of chemical reactions, known as the clotting cascade, then produces in a stringy mass of sticky protein called fibrin, which fills the gaps between the platelets. Over the next few days to weeks, as healing proceeds, the clot gradually dissolves and disappears in a process called lysis. Your scab falls off to reveal new skin underneath.

Balance between clotting and not clotting

Blood also must not clot to carry out its normal function of transporting oxygen and carbon dioxide and nutrients and waste. If blood clots occur inside blood vessels, they block blood flow and cause damage in surrounding tissues. Health problems like strokes and heart attacks, and clots in the heart, lungs and leg veins occur because local conditions like inflammation and slow blood flow trigger the clotting process. For example, when atrial fibrillation causes failure of atrial pumping, blood pools in the recesses of the upper chambers of the heart and clots may form.  Slow and turbulent blood flow in arteries narrowed by inflamed cholesterol plaques sets off the clotting process. Immobilization, bed rest or even prolonged sitting can promote clot formation in the leg veins.

Manipulation of the clotting system

Health problems like these, as well as the need to hasten clotting in some medical situations, drive attempts to manipulate the clotting system. Infusions of platelets and other blood products correct bleeding in the operating room and in medical conditions that lead to poor clotting, but, more commonly, medical problems require suppressing the blood clotting response. Most people are familiar with anti-clotting drugs, called “anticoagulants,” that interfere with one or more of the chemical processes in the clotting cascade. They are used for common heart problems like atrial fibrillation, leg vein clots and after heart valve replacements to prevent the foreign valve materials from triggering clotting. Most people are also familiar with “antiplatelet” drugs like aspirin used to help prevent heart attacks and strokes by interfering with the ability of platelets to start the clotting process. 

Pharmacological aid in breaking down clots 

A third type of intervention employing “thrombolytic” drugs aims to dissolve clots that have already formed.Thrombolytic drugs are used in hospitals, in the acute setting of clots that have caused heart attacks and strokes. When injected into arteries, they dissolve clot and restore blood flow though the problem area of the blood vessel that triggered the clotting process, or through an artery in the brain that has been suddenly blocked by a clot that traveled there from the heart.

Blood “thinners”

 Anticoagulant drugs are often incorrectly called blood thinners, but they do not change the thickness of blood. They block reactions in the clotting cascade. Heparin, when injected intravenously, causes the most direct and immediate interference, so doctors opt for this choice (or other similar drugs if a patient is allergic to heparin) when stopping clot formation is urgent. The insertion of an artificial heart valve, which will trigger clot formation on its surface, the presence of leg clots which may break off and travel to the lungs, or the onset of atrial fibrillation call for prompt blocking of clot formation, while the transition is made to oral anticoagulant drugs.

Oral anticoagulant drugs take a few days to slow the speed of blood clotting.  Of the oral drugs available for blocking clotting, coumadin is the oldest and most frequently used because its anticoagulant effects can be stopped quickly, if necessary. The ability to reverse anti-clotting effects is important if the anticoagulated patient develops a bleeding problem or is at risk of falling or other injury. Coumadin’s effects are reversed by intravenous injection of Vitamin K. People taking coumadin must have their blood checked regularly to monitor the rate at which the blood clots, and adjust doses accordingly. Other newer oral anticoagulants are popular because they do not require testing, but are more expensive and their effects cannot be reversed as quickly.  Intramuscular drugs are available for home use, usually when anticoagulation is a temporary treatment.

Drugs that make platelets less sticky

Antiplatelet drugs like aspirin and persantin are often prescribed to prevent clot formation in the coronary arteries, though the evidence about their benefits is mixed.  Far more common, however, is the unsuspected antiplatelet effect encountered by people using many over the counter products, particularly non-steroidal anti-inflammatory drugs (NSAIDS) used for pain, and some supplements like fish oil. Aspirin and NSAIDS are implicated in stomach bleeding episodes and in heavy menstrual bleeding.

 In addition to its role in repairing leaks and keeping blood running freely through the vast network of blood vessels in the body, the complex chemistry of the blood clotting system is revealing itself to be intricately involved in other aspects healing and in immune-mediated inflammatory states (such as COVID-19). The attempt to immunize against the SARS-COV2 virus has also focused attention on blood clotting, with the antigen chosen to stimulate antibody formation triggering serious adverse events involving both clotting and bleeding, as well as unsuspected clot formation in very small blood vessels. Knowledge is accumulating rapidly and, as it does, expect to see blood platelets revealed as much more than pieces of cells used to plug holes and the clotting system more closely related to the inflammatory system.  

The Legacy of Smallpox: Immunization

Imagine a virus spreading disease in your city. Imagine sending your children and other loved ones to a rural area to be injected with infected material taken from people ill with the virus. Imagine the injections making them sick, but not as sick as they might be from contracting the disease naturally. They will require a month for recovery, but, from that time, they will no longer have to fear the virus. You have now imagined exactly what happened at the start of the age of immunization. The time was the mid to late 1700s, the place was the colonies that would become the United States, and the epidemic was smallpox, a dangerous disfiguring illness. One of the families involved, in 1776, belonged to John Quincy Adams.

At the time, there was no FDA to regulate the treatment, known as variolation (from the Latin word variola meaning spotted).  People risked contracting severe cases of smallpox from the treatment, but they chose to go ahead because smallpox was a fearsome disease which, for centuries,  swept through both the Old and New Worlds in epidemic waves, appearing and disappearing, killing millions, scarring survivors, and changing history as the scourge laid armies low on one side or the other.

An idea with a long history

The idea that suffering a mild case of smallpox prevented a severe case arose independently in several different parts of the world, with the first written reports dating back to the mid-16thC in China. Cotton Mather, a Boston preacher, learned of the practice of deliberate infection from his African slave Onesimus in 1721 and introduced the practice to the Americas. Infected material or scabs from smallpox pustules were inhaled or scratched into the skin and while the practice killed 2-3% of the patients, that toll was considerably less than the 30% mortality rate of the epidemic disease.

How the variola virus causes smallpox

Pustules are the distinguishing marks of the disease called smallpox. The variola virus, whose only host is the human, enters the body via the mucous membranes of the mouth and nose. The virus multiplies quietly inside cells, producing no symptoms for 10-14 days. Then the body reacts with high fever, headache, and malaise. Patients take to their beds and develop a rash – at first, red spots, but then blisters which fill with pus.  They spread from the mouth and nose, over the face, down the trunk and extremities. Coughing and sneezing spew infected material from pustules into the air, spreading the disease to caretakers. Deep skin lesions leave permanent pocked marks such as those scarring the faces of George Washington and Abraham Lincoln. Unlike many other viruses, variola is fairly hardy outside the body, which enabled its transmission from contaminated blankets given to native Americans by the British during the French and Indian war. The virus also traveled downwind from hospital ships on the Thames River in England in the 1890s.

The role of milkmaids in the history of immunization

The next chapter in the history of immunization occurred in Britain, where the fabled, beautiful skin of milkmaids was attributed to resistance to smallpox, conferred by prior infection with cowpox, a milder disease now known to be caused by the vaccinia (meaning cow) virus. In the late 1700s, Edward Jenner, a Gloucestershire physician, successfully prevented small pox by prior inoculations with the material from cowpox infections. The inoculations were called vaccinations, and Jenner became “the father of vaccination.”

Elimination of smallpox

The cowpox vaccine evolved over time into the standard vaccination procedure which eventually resulted in the elimination of the smallpox virus from the human population in the mid-1900s. The last natural case occurred in Somalia in 1977. Smallpox vaccinations, which had significant adverse effects in 1-2% of the population, were discontinued in the US in 1972 and the WHO declared smallpox eliminated from the world in 1980. Variola is the first and only virus to have been eliminated as a source of human illness, but other infectious diseases have been tamed in similar fashion and the hope is that new ways of creating vaccines will be even more effective.

How vaccines work

Smallpox vaccines were made from whole, live vaccinia viruses. Some vaccines for other diseases come from attenuated viruses (weakened viruses that transmit disease less effectively), or from killed viruses. Some vaccines are directed not at viruses, but at bacteria or at toxins like those produced by the diphtheria bacteria. All of them induce the immune system to create a memory of the specific organism or toxin, which will protect against future infection with the organism or the effects of a toxins like the ones produced by tetanus or diphtheria bacteria.

Because the immune reaction to infection is complicated and involves many types of immune cells as well as production of antibodies to the infecting organism, immunity to future infection is best induced and longest lasting after actual infection. Immunity after smallpox infection is lifelong, but lasts only 5-7 years after smallpox immunization. Other vaccines, especially those made from live organisms, are very effective and, some provide lifelong protection, especially with periodic booster doses. They have made infections like polio, measles, diphtheria, whooping cough and tetanus so rare that many doctors have never seen such illnesses.    

New technology

Like variolation, vaccines that rely on whole organisms can cause serious and unintended consequences. In the last two decades, genetic technology has enabled researchers to create vaccines from small parts of disease-causing organisms like COVID-19 or hepatitis viruses. Since sequencing genomes became automated and less expensive, the world of genetic virology and bacteriology has exploded. It is no longer necessary to rely on tedious and technically difficult culture methods to grow and identify microscopic and submicroscopic organisms. And it is possible to break down genetic information and use it to artificially produce components of these organisms or the proteins they produce, employing stock materials off laboratory shelves.

Using genetic material from viruses, researchers get living cells in laboratories to produce proteins specified by those genes and then create vaccines from the proteins. Or they inject the genetic material directly into people to get their cells to make the proteins. The immune system then recognizes these proteins as foreign and creates antibodies and memory cells against them. Theoretically, the induced immune memory prevents infection should the vaccinated person encounter the virus.  But much work remains. Some of the vaccines tried do not produce robust or long lasting immunity. Some have had paradoxical effects, with the immunized individual responding to actual infection with worse disease, as if a small amount of immunity actually enhanced the ability of the live virus to cause illness. The widespread deployment of the new COVID-19 vaccines – apparently effective in test groups over a relatively short testing period (safety studies in the past have run for years) will provide an enormous amount of information as to long-term safety and efficacy over years to come. This will be the largest and most public trial so far for the vaccine industry’s newest technologies. If the results are as good as the researchers who have developed them expect them to be, you can expect more and more vaccines to appear on the market.

 In the meantime, smallpox virus samples still exist in the US and in Russia. If these stocks had been eliminated, as once was planned, the smallpox virus would truly have disappeared from the world because, unlike most of the viruses that plague us, the small pox virus has no other animal hosts. And while there are long term plans to create new smallpox vaccines, it would be wise, in this uncertain world, to maintain the ability to rapidly understand the genetic makeup of the smallpox virus, as well as to rapidly implement old-fashioned smallpox immunization.

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