Inflammation Everywhere

When I started as a practitioner, I understood inflammation to mean an acute response to trauma (e.g., tissue-penetrating injury) or a pathogen (e.g., streptococcal bacteria). This response consisted of a plasma cellular component, a vascular effect and immune system participation. The immediate granulocyte cellular involvement is primarily by neutrophils, and under certain circumstances basophils or eosinophils, followed by mononuclear macrophages. Vasodilation occurs first at the arteriole level, followed by capillary dilation, resulting in edema and a net increase in plasma components to neutralize and phagocytize pathogens and foreign material. The associated innate immunity cytokines and other factors released are immediately available and non-intruder specific. As a medical student, I had memorized the five Latin diagnostics of inflammation: rubor, tumor, calor, dolor and functio laesa. As a doctor, I treated acute inflammation with antibiotics and, if purulent, with drainage.

Chronic Inflammation

I was soon introduced, in my professional career, to the concept of chronic inflammation as the basis of certain lifelong diseases: rheumatoid arthritis, diverticulitis, asthma and others. The five diagnostic symptoms and signs of acute inflammation are, to some degree, present; however, they do not resolve and, in one manner or another, persist for a lifetime. In chronic inflammation, the dominant cell type is the macrophage, the vascular response is angiogenesis, and the immune response becomes more complex and antigen/antibody specific. Rather than resolution, chronic inflammation progresses to fibrosis, at times granulomatous, and tissue destruction with functional impairment.

At first, we treated these diseases with analgesics and antipyretics, such as aspirin, subsequently with steroids, nonsteroidal anti-inflammatories, and more steroids. We rarely cure any of these afflictions; we treat the pathology, not the cause, and we hope to make the patient more comfortable.

Inflammatory Diseases

By the turn of the century, the causative concept of inflammation became ubiquitous. Atherosclerosis no longer was considered primarily a passive disease of cholesterol lipid deposition engendering a foreign body response and plaque formation, but a continuously active process of pro-inflammatory low-density lipoprotein (LDL) excitation of the vascular endothelium, resulting in recruitment of monocytes and T cells, leading to the release of cytokines, proteases and vasoactive molecules. The immune mechanisms of the body counter with an anti-inflammatory response, which can be greatly aided by lowering the circulating LDL-cholesterol substrate. Thus, our lifestyle, diet, pharmaceutical and surgical lowering of LDL cholesterol markedly reduces the most crucial atherosclerotic raw material; it is not, however, curative therapy for the underlying inflammatory cause of atherosclerosis.

Type 1 diabetes is stated to be an autoimmune disease of pancreatic beta cells manifested by inflammation with eventual beta-cell destruction and cessation of insulin production. Most of the scientific community postulates peripheral insulin resistance as the primary cause of type 2 diabetes, although there is solid evidence to support pancreatic islet cell dysfunction as the causative agent with insulin resistance being a secondary defense mechanism. The inflammation proponents of diabetes ideology cite the presence in both type 1 and type 2 diabetes of the cytokine proteins interferon, (IFN)-gamma, IFN-alpha and interleukin (IL)-1 beta, characteristically implicated in the pathogenesis of inflammation. The therapeutic use of anti-inflammatories with moderate palliative success is given as further evidence for the inflammatory nature of diabetes.

Once obesity was accepted as a disease and the mechanisms of success of metabolic/bariatric surgery as neurohormonal and not simply caloric deprivation, obesity was considered a multifactorial inflammatory process. This reasoning was again based on the presence of multiple inflammatory markers derived from or elicited by the gut, neurologic transmitters, adipocytes, the intestinal biomere and even bile salt composition. Similarities of inflammatory patterns in obesity, diabetes, hypertension and hyperlipidemia, as well as clinical kinship, gave rise to this cluster of pathology to be designated as the metabolic syndrome.

Cancer, once characterized as a cellular mutation gone unchecked, with certain cancers founded on genetic (BRCA breast cancers) and environmental (smoking) causes, metamorphosed to being designated an inflammatory process. This concept is based on the belief that cellular proliferation alone does not cause cancer but that the mutation to malignancy is sustained by a receptive environment rich in inflammatory cells, growth factors, activated stroma and DNA-disruptive agents. Innate anti-inflammatory factors and immunity-triggered cancer-killing cells may become generated and try to annihilate the cancer. The outcome of this battle can destroy a patient’s cancer, result in a curable cancer by surgery and/or nonsurgical therapy, or evade current modes of intercession with a fatal outcome.

Agents of Inflammation and Anti-Inflammatories

In addition to the presence of acute and chronic inflammation cellular elements (e.g., neutrophils, macrophages), there are a plethora of mediating agents involved in the inflammatory process. They consist of cytokines (i.e., signaling peptides) IL-1 beta, IL-6, tumor necrosis factor-alpha that cause receptor activation, which elicits intracellular signaling pathways including mitogen-activated protein kinase, nuclear factor kappa B and Janus kinase–signal transducer and activator of transcription pathways. There are at least five transcription factors, several serine/threonine protein kinases, many other cytokines, inflammatory proteins (e.g., C-reactive protein), haptoglobins, serum amyloid A, fibrinogen and 1-acid glycoprotein, as well as certain activated enzymes (e.g., inducible nitric oxide synthase), all involved in various aspects of the inflammation cascade.

Numerous complex schemas of elucidation, progression, interaction and perpetuation of inflammation have been produced, primarily as a scholarly exercise and not too beneficial in the real world of patient care. In these schemas, there are also body-produced anti-inflammatories, such as the pituitary adrenocorticotropic hormone–stimulated adrenal glucocorticoids that counteract the pro-inflammatory agents and prevent an overwhelming inflammatory response and death of the individual. When this balance of chronicity fails, a fatal cytokine storm may ensue.

In treating inflammation as a general or specific condition, in addition to pharmaceutical steroids, aspirin and nonsteroidal anti-inflammatories, certain foods with anti-inflammatory properties have been advocated, such as fish oils containing alpha and omega-3 fatty acids. Homeopathic preparations and questionable anti-inflammatory enemas have also found some popularity in the community.

What Does It All Mean?

With regard to acute inflammation, except for extirpation of foreign bodies, our heritage from caveman days of draining abscesses has largely been supplanted by judicious use of antibiotics and image-assisted drainage by our radiology colleagues. Our current insight into chronic inflammation and anti-inflammatories has, however, served us well. The flagrant chronic inflammation of certain diseases has stimulated palliative, at times even curative, anti-inflammatory therapies. Conceptualization of underlying inflammation in the primary chronic afflictions of humanity—obesity, diabetes, atherosclerosis, cancer—may be beneficial in our understanding of the processes involved and pathways for the evolution of new therapies.

Recently, inflammation has engendered great interest in explaining the clinical manifestations of COVID-19 and in treating them. The most susceptible individuals to contract severe COVID-19, requiring ICU admission, are the older patients and those with certain chronic disease states: cardiovascular, renal, diabetes, hypertension and obesity. This cohort harbors chronic inflammation and is more prone to exhibit a severe acute inflammatory response when infected with COVID-19, which may elicit a cytokine storm. Patients who recover from the acute infection can exhibit chronic inflammatory manifestations, such as myocarditis. Appreciation of the role of inflammation in the pathogenesis of COVID-19 has been responsible for instituting steroid anti-inflammatory therapy, which undoubtedly has saved many lives, shortened hospitalization for survivors and possibly dampened post–COVID-19 sequelae.

Can inflammation, however, be as ubiquitous as current concepts would proclaim it to be? Is inflammation the progenitor of all diseases? I remember that in the 1980s the scientific world became enamored with the free radical nitric oxide because this substance seemed to be present in nearly every body response. Nitric oxide subsequently lost favorable enthusiasm and is rarely mentioned today by theorists of functional mechanisms.

The identification of a multiplicity of agents, factors, processes, relationships, balances and imbalances does not equal understanding of causes and governing mechanisms. Although they both produce flames, smoke and heat, a forest fire is different from burning oil on top of water; a lightning strike is not the same as a gas leak near a flame. What we know today about inflammation is not grounds for complacency but stimulus for curiosity, thought and research. We have just started the journey of truly understanding inflammation.

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Dr. Buchwald is a professor of surgery and biomedical engineering, and the Owen H. and Sarah Davidson Wangensteen Chair in Experimental Surgery (emeritus), at the University of Minnesota, in Minneapolis. His articles appear every other month.

This article is from the August 2021 print issue.