248 LEADER Br J Sports Med: first published as 10.1136/bjsm.2003.011221 on 21 May 2004. Downloaded from Advances in microscopy and cell ...... biology in the 19th century gave rise to cell based definitions of inflammation (table 2). This represented a completely What is ‘‘inflammation’’? Are we novel way of understanding and defin- ing inflammation. By the end of the ready to move beyond Celsus? 19th century it was acknowledged that changing cell populations arising from A Scott, K M Khan, J L Cook, V Duronio both the blood and local proliferation were a key feature of many models of ...... inflammation.6 With the advent of the microscope, such a complexity of events Different definitions of inflammation are a cause for concern underlying inflammatory reactions was revealed that researchers began to ques- nflammation, a term coined by the such as a macroscopic tear of ligament tion whether inflammation was indeed ancients, is widely used in sports or muscle. Thus, in its genesis, inflam- a single process. A prominent German Imedicine. But what is meant when a mation was defined by a combination of biologist, Neumann, defined inflamma- clinician tells a patient that symptoms clinical signs and symptoms not by tion more loosely as a ‘‘series of local are probably due to inflammation? The specific pathophysiology (table 1). phenomena developing as the result of question of whether inflammation is Defining inflammation according to primary lesions to the tissues and that helpful or harmful to healing can only clinical signs and symptoms has major tend to restore their health’’.1 be answered after inflammation is limitations, as in most cases the cellular In one sense, the most cited sports defined. This brief analysis of inflam- processes and signals that underlie the medicine model could be seen as an mation reveals that the term’s definition cardinal signs occur at a subclinical level elaboration of this 19th century vessel- has changed dramatically since it was and do not give rise to any heat, redness, cell hierarchy.7 In the classic monograph first used by Celsus nearly 2000 years swelling, or pain.3 For example, the Sports-induced inflammation, Leadbetter7 ago. The definition also depends on inflammation of delayed onset muscular describes a stereotyped cellular response the type of lens the viewer is using soreness may cause tenderness on pal- that follows trauma to vessels. These —whether it be clinical, cellular, or pation or mild discomfort,4 but no red- phases progress from activation of pla- molecular. ness or swelling. Broadening the telets and endothelium, through recruit- definition of inflammation to include ment and activation of leucocytes, to INFLAMMATION—WIDELY USED one or a subset of the cardinal signs is proliferation and repair by endothelium (AND ABUSED) not a solution, as areas of swelling, pain, and fibroblasts. In this view, inflamma- On the one hand, the label inflamma- and tenderness may have a wide variety tion is defined as a necessary phase in tion is ascribed to a wide range of of non-inflammatory causes. For exam- the repair response after an injury in 7 potential presentations in musculo- ple, regions of muscle spasm (some- which the vessels are disrupted. skeletal medicine, but on the other, times called ‘‘myositis’’) and many cases few clinicians would be able to define of tendinosis (often called ‘‘tendinitis’’5) INFLAMMATION TODAY: A this complex biological cascade any are often confused with inflammation, COMPLEX CASCADE http://bjsm.bmj.com/ better than Cornelius Celsus did in the because of the local pain and swollen Modern molecular biology superimposes 1st century AD. Nevertheless, this limited nature of the tissue. additional layers of complexity on this understanding of pathobiology does not Two centuries after Celsus, Galen was commonly accepted model. Firstly, a limit therapeutic enthusiasm; American influential in promoting the humoral tissue may be influenced by proinflam- physicians prescribe drugs to block view of inflammation. In his model, matory signalling molecules, even in the inflammation at a rate that costs inflammation (and pus specifically) was absence of inflammatory cell invasion. patients over a billion US dollars part of the beneficial response to injury, For example, chondrocytes respond to a annually. There has been an explosion 1 rather than a superimposed pathology. proinflammatory , interleukin on September 27, 2021 by guest. Protected copyright. of knowledge about inflammation over This humoral view of inflammation 1, which is released by synoviocytes, to the second half of the 20th century, yet persisted into the 19th century when catabolise the surrounding cartilage our clinical concepts about inflamma- the fifth cardinal sign—function laesa, matrix by upregulating their expression tion have remained relatively resistant loss of function—was added in 1871 by of matrix metalloproteases.8 This carti- to change. This leader highlights the Virchow (table 1). In contrast with lage degeneration occurs in the absence evolution of the term inflammation as a Galen, however, Virchow viewed inflam- of inflammatory cells. Secondly, aspects prelude to a detailed update of modern mation as inherently pathological.2 of both inflammation and repair can be concepts relevant to sports induced inflammation. Table 1 Cardinal signs of inflammation A HISTORICAL PERSPECTIVE The word inflammation comes from English Latin Cause the Latin inflammare (to set on fire). Heat Calor The Roman Celsus is credited as first Redness Rubor Vasodilation documenting (1st century AD) the four Swelling Tumor Increased vascular permeability cardinal signs of inflammation: rubor et Increased granulation tissue Pain Dolor Physical and chemical stimulation of nociceptors tumor cum calore et dolore (redness and Loss of function Functio laesa Pain 12 swelling with heat and pain). This Reflex muscle inhibition definition of inflammation recognises Disruption of tissue structure what we would today know as a ‘‘class- Fibroplasia and metaplasia ical’’ acute inflammatory response—for example, following a traumatic event

www.bjsportmed.com LEADER 249 Br J Sports Med: first published as 10.1136/bjsm.2003.011221 on 21 May 2004. Downloaded from

Table 2 Key advances in developing a definition of inflammation between 1st and 20th centuries AD

Author, year Quotation Historical interpretation Modern significance

Celsus, 1st century AD ‘‘rubor et tumor cum calore et dolore’’ First documentation of cardinal signs of Emphasised the importance of clinical inflammation observations rather than philosophy based medicine Galen, 3rd century AD ‘‘Laudable pus’’ Infection and inflammation are beneficial Inflammation was seen as an expression to repair of wounds of humoral theory well into the 19th century Virchow, 1871 ‘‘The inflammatory reaction is a Inflammation as a pathological Recognised cellular nature of consequence of an excessive intake by proliferation of cells due to leakage of inflammatory response interstitial cells, of food…filtering nutrients from vessels through the vessel wall’’ Cohnheim, 1873 ‘‘Finally…there lies outside the vessel…a Blood corpuscles were seen as First description of diapedesis colourless blood corpuscle.’’ pathological mechanisms by which infections spread, secondary to vascular injury Metchnikoff, 1908 ‘‘the primum movens of the Inflammation as a defensive cellular First to express the view that phagocytes inflammatory reaction is a digestive response to pathogens, guided by the were protective, not pathological action…toward the noxious agent’’ vessels rather than an aspect of the pathology itself Lewis, 1927 Inflammation as the ‘‘triple response’’ Inflammation is characterized by vascular First recognition of neurogenic to injury events mediated both by local chemicals inflammation; first physiological and by axons characterisation of vascular events Rocha e Silva, 1974 Inflammation as a ‘‘multi-mediated Inflammation defined by mediators Biochemical definition of inflammation phenomenon, of a pattern type in which all mediators would come and go at the appropriate moment…increasing vascular permeability, attracting leucocytes, producing pain, local edema and necrosis’’

triggered and modulated by primary despite the knee jerk reaction for many 3 Gallin JI, Snyderman R. Overview. In: Gallin JI, Snyderman R, eds. Inflammation: basic events occurring outside the vascula- patients to self administer these com- principles and clinical correlates, 3rd ed. ture, such as vibration, hypoxia, and pounds. In summary, this leader shows Philadelphia: Lippincott Williams & Wilkins, mechanical loading. Mast cells degra- that (a) inflammation is not a single 1999:1–4. 4 MacIntyre DL, Reid WD, McKenzie DC. Delayed nulate in response to hypoxia or process and (b) it is not simply binary in muscle soreness. The inflammatory response to vibration, triggering an inflammatory nature (‘‘on’’ or ‘‘off’’), but it can be muscle injury and its clinical implications. Sports response independently of modulated by many factors in the cell’s Med 1995;20:24–40. 9 environment. There remains a great deal 5 Khan KM, Cook JL. Overuse tendon injuries: and platelet activation. Mast cell where does the pain come from? Sports Med degranulation can trigger neurogenic of scope for understanding how Arthrosc Rev 2000;8:17–31. inflammation. Hypoxia can also cause mechanical loading (exercise as either 6 Cotran RS. Inflammation: historical perspectives.

sport or rehabilitation) influences the In: Gallin JI, Snyderman R, eds. Inflammation: http://bjsm.bmj.com/ increased expression of vascular endo- basic principles and clinical correlates, 3rd ed. thelial growth factor, which can reduce many faces of the complex cascade that Philadelphia: Lippincott Williams & Wilkins, the patency of vessels, leading to is inflammation. 1999:5–10. oedema, and stimulate neovascularisa- 7 Leadbetter WB. An introduction to sport-induced Br J Sports Med 2004;38:248–249. soft-tissue inflammation. In: Leadbetter WB, 10 tion. The response of cells to mechan- doi: 10.1136/bjsm.2003.011221 Buckwalter JA, Gordon SL, eds. Sports-induced ical loading may also be able to inflammation. Park Ridge, IL: American Academy modulate their inflammatory response...... of Orthopaedic Surgeons, 1989:3–23. 8 Pelletier JP, Martel-Pelletier J, Abramson SB. Tensile loading of human tendon fibro- Authors’ affiliations Osteoarthritis, an inflammatory disease: blasts can reduce their expression of A Scott, K M Khan, V Duronio, University of potential implication for the selection of new on September 27, 2021 by guest. Protected copyright. inflammatory —for example, British Columbia, Vancouver, Canada therapeutic targets. Arthritis Rheum J L Cook, La Trobe University, Victoria, 2001;44:1237–47. interleukin 1, tumour necrosis factor 9 Soter NA, Wasserman SI. Physical urticaria/ Australia a—while causing a modest increase in angioedema: an experimental model of mast cell E2 release.11 12 activation in humans. J Allergy Clin Immunol Correspondence to: Professor Khan, 1980;66:358–65. Department of Family Practice, University of 10 Griffioen AW, Molema G. Angiogenesis: potentials for pharmacologic intervention in the CLINICAL IMPLICATION British Columbia, Suite 211, 2150 Western Parkway, Vancouver, British Columbia V6T treatment of cancer, cardiovascular diseases, and The clinical implication is that the term chronic inflammation. Pharmacol Rev 1V6, Canada; [email protected] inflammation embraces a great variety 2000;52:237–68. 11 Wang JH. IOC Workshop on Tendinopathies, of biological processes. Whether inflam- Athens, Greece, 2003. mation is involved in a patient’s symp- REFERENCES 12 Almekinders LC, Banes AJ, Ballenger CA. Effects toms is not a straightforward question. 1 Rocha e Silva M. A brief survey of the history of of repetitive motion on human fibroblasts. Med Knowing whether an anti-inflammatory inflammation. 1978. Agents Actions Sci Sports Exerc 1993;25:603–7. 1994;43:86–90. 13 Stovitz S, Johnson R. NSAIDs and musculoskeletal drug is likely to benefit or harm a 2 Benaroyo L. [How do we define inflammation?]. treatment: what is the clinical evidence? Phys patient’s healing response is complex13 Schweiz Rundsch Med Prax 1994;83:1343–7. Sportsmed 2003;31:21–7.

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