General Pathology Series: Inflammation - Historical Perspectives

Foreword

Inflammation is a vital reaction mechanism to threats, and it is part of a beneficial defense system that has evolved and been conserved evolutionarily over thousands of years. But why is this process associated with diseases? While inflammation is primarily protective and helps maintain tissue equilibrium, uncontrolled inflammation can become detrimental, leading to the progression of chronic inflammatory diseases. This series aims to provide a comprehensive understanding of the inflammatory process by emphasizing its historical context, intricate mechanisms, and events that will determine its end or the development of diseases. Through six captivating chapters, readers will obtain a holistic perspective on inflammation and its significance in health and disease.

1. General Pathology Series: Inflammation - Historical Perspectives

2. General Pathology Series: Inflammatory Cells and Mediators

3. General Pathology Series: Inflammatory Cells Recruitment and Clearance

4. General Pathology Series: Resolution of Inflammation

5. General Pathology Series: Acute vs. Chronic Inflammation

6. General Pathology Series: Inflammatory Diseases

Introduction

Pathology is the branch of medicine that studies the origins and nature of diseases. Pathological conditions (abnormal or diseased states) often involve inflammation as a key component. Although it seems contradictory, the primary function of inflammation is to protect the body from microorganisms or particles and prevent diseases. When the body detects the presence of harmful stimulus, which may be non-infectious in nature like heat or a chemical substance, or infectious like microorganisms (viruses, bacteria, fungus), it initiates an inflammatory response. Inflammation is a complex process orchestrated by various cells and molecules of the immune system (body's defense system), which results in the appearance of clinical signs such as pain, fever, swelling, among others. The history of inflammation encompasses centuries of observations, theories, and scientific discoveries, which will be explored in detail below.

Early Times

The word inflammation comes from the Latin inflammare which means “to set on fire”. One of the first documentations of the inflammatory process comes from ancient Greece. Hippocrates (460 BC–370 BC) proposed the theory of the four humors (blood, yellow bile, black bile, and phlegm), which stated that an imbalance of bodily fluids could cause inflammation and other illnesses (Figure 1) (Scott, Khan, Cook, & Duronio, 2004).

Figure 1. The theory of the four humors. The Greek Hippocrates believed that the body was made up of four main components or Four Humors. These Four Humors needed to remain balanced in order for individuals to remain healthy. (Schools history org., n.d.)

Later in the first century, the Roman Cornelius Celsus (25 BC–AD 50), wrote a broad encyclopedia that covered a variety of topics, some of which had a medical focus De Medicina, an eight-volume compendium. It was the most important medical manuscript after the writings of Hippocrates. The work of Cornelius Celsus, which had been neglected for several centuries, was found in 1443 by Pope Nicolas V and it was the first medical and surgical book to be printed (AD 1478). Cornelius Celsus first documented what is known as the four cardinal signs of inflammation (Figure 2): calor (heat), rubor (redness), tumor (swelling), and dolor (pain) (Kockerling, Kockerling, & Lomas, 2013). This definition of inflammation recognizes what is now recognized as a "classic" acute inflammatory response, which occurs following events like trauma or injury. The term "acute" indicates that it is of short duration, typically lasting for hours or days, and resolves naturally. Thus, inflammation initially characterized by Cornelius Celsus was based on observable signs and accompanying clinical symptoms.

Figure 2. Cardinal signs of inflammation. This cartoon depicts five Greeks representing the cardinal signs of inflammation heat, redness, swelling, pain and loss of function. The fifth sign loss of function (functio laesa) was incorporated in 1858 by Rudolf Virchow. (Lawrence, Willoughby, & Gilroy, 2002)

Galen, who lived two centuries after Celsus, made contributions to the development of the humoral theory of inflammation, initially proposed by Hippocrates. Like Hippocrates, Galen proposed that imbalances in the body's four humors (blood, phlegm, yellow bile, and black bile) led to disease and inflammation. When one humor predominated, disease developed. The excess fluid was removed by bleeding (blood) or purgative (bile). In his theory, inflammation was a necessary component of the healing response to damage. Also, he did not consider 'pus' to be harmful, which gave rise to the concept of "laudable pus", which must be allowed to exit through an incision. Up until the Renaissance (which ran from the 14th through the 17th century), the theory of the 'humors' was a recognized medical practice (Hajar, 2021).

18-19th Centuries

In the 18th century, the humoral disease paradigm started to change when Albrecht Von Haller (1708-1777) investigate the toxic properties of decaying tissue to determine why it causes disease when present in live animals (1761). Von Haller noted that experimental animals developed fevers and other symptoms of disease when given putrid fluids by intravenous injection or oral ingestion derived from decaying organic matter while extracts from organic matter did not cause febrile symptoms. Later research by François Magendie (1783–1855) demonstrated that experimental animals developed disease symptoms after receiving an intravenous injection of decomposing meat (1823). The pioneering research by Von Haller and Magendie challenged the prevailing belief that imbalances in bodily humors were the sole cause of disease. Instead, they made substantial contributions for the understanding that toxic substances, arising from putrefaction and decay, could have detrimental effects on living organisms, leading to inflammation and illness (Martins, Ribeiro-Gomes, & Daniel-Ribeiro, 2023).

The 19th century witnessed significant advances in microscopy and cell biology, which revolutionized our understanding of inflammation. These breakthroughs paved the way for the development of cell-based definitions of inflammation, representing a novel approach to comprehending and defining this complex biological process. In the mid-19th century, a German physician, Rudolf Virchow, proposed the cellular theory of inflammation, suggesting that diseases originate at the cellular level and that inflammation occurs due to changes in the cells present at the site of injury (Figure 3) (Medzhitov, 2010).

Figure 3. Rudolf Virchow in 1886 alongside an original illustration of his cell theory. (All thats interesting, n.d.)

Rudolf Virchow also proposed a fifth cardinal sign of inflammation in 1858, known as "functio laesa", loss of function (represented in Figure 1). Virchow suggested that the dysfunction of the tissue and organs affected by the inflammatory process should also be considered as a key characteristic of inflammation, in addition to the classical four signs of inflammation (redness, heat, swelling, and pain). Virchow regarded inflammation as inherently harmful in nature, causing disease or abnormal conditions. During the same period, French physiologist Claude Bernard (1813-78) introduced the concept of homeostasis (the ability of an organism or system to maintain internal stability and balance despite external changes or fluctuations) and described inflammation as a defense mechanism to restore the body's equilibrium (Scott et al., 2004).

20th-21st Centuries

In the early 20th century, Russian immunologist Elie Metchnikoff discovered an important process mediated by immune cells, which play a crucial role in inflammation called phagocytosis (Gordon, 2016). Phagocytosis is the ability of certain cells to engulf and destroy invading microorganisms or foreign particles. His work earned him the Nobel Prize in Physiology or Medicine in 1908. Metchnikoff expanded the cellular theory of inflammation, which states that immune responses are mediated by cells rather than humoral factors. The idea that inflammation was harmful to the host was the most prevalent at that time, being defended by most experts in the field. Metchnikoff played a very important role in the history of inflammation by demonstrating to other specialists that this view was inappropriate and that inflammation was a beneficial defense mechanism for organisms (Gordon, 2016). The main definitions of inflammation between the 1st and 20th centuries AD are listed in Table 1.

Table1. Key advances in developing a definition of inflammation between the 1st and 20th centuries AD. (Scott et al., 2004)

In the first half of the 20th century, researchers discovered and characterized important mediators of inflammation: prostaglandins, histamine, and leukotrienes. In 1939, prostaglandins were identified in human semen by the Swedish physiologist Ulf von Euler, who named them, thinking that they were secreted by the prostate gland (Igic, 2018). The histamine was described in 1910 by Dr. Henry Dale, a British pharmacologist, and his colleagues (Tiligada & Ennis, 2020). The leukotrienes were discovered by Bengt Samuelsson in 1938, who shared the distinguished Nobel Prize in Medicine with his former mentor Sune Bergström and with the British pharmacologist Sir John Vane in 1982 (Serhan & Wasserman, 2006). Vane, in the 1960s, discovered the role of prostaglandins in inflammation and their inhibition by aspirin-like drugs (fever reducers and pain killers).

In 1989, Charles Janeway Jr. introduced the concept that the initiation of an immune response is primarily triggered by the presence of specific molecules found in microorganisms. These molecules were later recognized as Pathogen-associated molecular patterns (PAMPs). PAMPs were identified as capable of activating receptors present in the cells of the immune system. Janeway named these receptors "molecular pattern recognition receptors" (Janeway, 1989). Some years later, Poli Matzinger proposed that, during an infection when tissue is damaged, certain molecules that are typically inside the cells are released, like DNA for instance. Matzinger suggested that these molecules serve as a "danger signal" activating the immune system in a similar manner to foreign molecules (Matzinger, 1994). This led to the formulation of the concept known as danger-associated molecular patterns (DAMPs). This new concept expanded our understanding of the immune response by highlighting the importance of tissue damage and the release of endogenous molecules in triggering an immune reaction. The concept of DAMPs has since influenced research and the understanding of various diseases, including autoimmune disorders, cancer, and sterile inflammation (when microorganisms are not involved).

Advances in molecular biology pushed this field forward. In 1996, a researchers made a significant discovery by demonstrating that fruit flies (Drosophila) required specific genes called Toll genes to effectively combat fungal infections (Lemaitre, Nicolas, Michaut, Reichhart, & Hoffmann, 1996). A year later, Ruslan Medzhitov (a postdoc of Charles Janeway Jr.) successfully cloned and characterized a human counterpart of the Drosophila Toll gene (Medzhitov, Preston-Hurlburt, & Janeway, 1997). These findings led to the identification of Toll-like receptors (TLRs) in humans. Currently, there are 10 TLRs known in humans and 12 in mice (Figure 4) (Martins et al., 2023). TLRs belong to a class of pattern recognition receptors (PRRs) initially described by Janeway in 1989. These receptors have the ability to recognize and bind to molecules that are widely shared by pathogens (known as pathogen-associated molecular patterns or PAMPs) as well as intracellular molecules such as DNA released during tissue damage (known as damage-associated molecular patterns or DAMPs). Toll-like receptors are essential components of the immune system that recognize foreign (PAMPs) or dangerous (DAMPs) molecules and trigger immune responses (Martins et al., 2023; Noh, Yoon, Kim, Choi, & Jung, 2020).

Figure 4. Human TLRs. TLR members can be divided into cell surface types (TLR1, 2, 4, 5, and 6) and intracellular types (TLR3, 7, 8, and 9). (Noh et al., 2020)

Recent advancements in cell biology, molecular biology, and genetics have furthered our understanding of inflammation. Scientists have identified, and are still unraveling, various signaling pathways, inflammatory mediators, and mechanisms of immune cells involved in the inflammatory response. Therapeutic interventions targeting inflammation, such as anti-inflammatory drugs and therapies that regulate the immune system, have been developed and continue to be investigated. A promising discovery is the pro-resolving mediators, a category of natural molecules produced by our own bodies that play a vital role in resolving inflammation and facilitating tissue repair following an inflammatory response (Lawrence et al., 2002). These findings open the option of developing more efficient drugs to treat chronic diseases or even cancer, which could offer a new and complementary approach to conventional treatments, potentially surpassing them in their ability to regulate inflammation and restore optimal tissue function.

Conclusions

The history of inflammation reflects a gradual progression in our understanding of this complex biological response, from ancient observations to modern scientific discoveries. It is clear that certain discoveries throughout history were made possible by significant technological advancements in the field. The study of inflammation allows us to delve deeper into this process, leading to a greater understanding of its involvement in the development of diseases and paving the way for advancements in the field, that can result in more efficient therapies. By exploring the mechanisms of inflammation, researchers can improve their understanding and drive innovation to combat diseases more effectively.

References

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Hajar, R. (2021). Medicine from Galen to the Present: A Short History. Heart Views, 22(4), 307-308. DOI: https://doi.org/10.4103/heartviews.heartviews_125_21

Igic, R. (2018). Remembrances of Ulf Svante von Euler. Acta Physiol (Oxf), 224(3), e13098. DOI: https://doi.org/10.1111/apha.13098

Janeway, C. A., Jr. (1989). Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol, 54 Pt 1, 1-13. DOI: https://doi.org/10.1101/sqb.1989.054.01.003

Kockerling, F., Kockerling, D., & Lomas, C. (2013). Cornelius Celsus--ancient encyclopedist, surgeon-scientist, or master of surgery? Langenbecks Arch Surg, 398(4), 609-616. DOI: https://doi.org/10.1007/s00423-013-1050-0

Lawrence, T., Willoughby, D. A., & Gilroy, D. W. (2002). Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol, 2(10), 787-795. DOI: https://doi.org/10.1038/nri915

Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M., & Hoffmann, J. A. (1996). The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell, 86(6), 973-983. DOI: https://doi.org/10.1016/s0092-8674(00)80172-5

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Medzhitov, R., Preston-Hurlburt, P., & Janeway, C. A., Jr. (1997). A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature, 388(6640), 394-397. DOI: https://doi.org/10.1038/41131

Noh, J. Y., Yoon, S. R., Kim, T. D., Choi, I., & Jung, H. (2020). Toll-Like Receptors in Natural Killer Cells and Their Application for Immunotherapy. J Immunol Res, 2020, 2045860. DOI: https://doi.org/10.1155/2020/2045860

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Visual Sources

Figure 1: Schools history org., (n.d.). Theory of the Four Humours. [image]. Retrieved June 27, 2023, https://schoolshistory.org.uk/topics/medicine-through-time/medicine-in-ancient-greece/theory-of-the-four-humours/

Figure 2: Lawrence, T., Willoughby, D. A., & Gilroy, D. W. (2002). Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol, 2(10), 787-795. [image]. DOI: https://doi.org/10.1038/nri915

Figure 3: All thats interesting, (n.d.) (2019). Meet Rudolf Virchow, The Victorian “Pope Of Medicine” Who Didn’t Believe In Evolution. [image]. Retrieved June 27, 2023, https://allthatsinteresting.com/rudolf-virchow

Figure 4: Noh, J. Y., Yoon, S. R., Kim, T. D., Choi, I., & Jung, H. (2020). Toll-Like Receptors in Natural Killer Cells and Their Application for Immunotherapy. J Immunol Res, 2020, 2045860. [image]. https://doi.org/10.1155/2020/2045860