- CARDINAL SIGNS (the "four ORs:" rubor, tumor, calor, dolor)
- INFLAMMATORY (LEUKOCYTIC) INFILTRATE
- Examples of inflammation in skin and overview of lymphatic system.
Microscopically, inflammation shows up most clearly as increased numbers of white blood cells
(i.e., the inflammatory infiltrate which results from emigration of leukocytes).
- Recent Research
The inflammatory response is very familiar. TRY IT YOURSELF: A mild example can be produced at your convenience. Firmly scrape the skin on your forearm, and then watch as redness (with possibly some mild swelling and heat) develops over the next few minutes.
Inflammation is characterized by several familiar signs, redness, swelling, heat and pain. To understand inflammation is to understand how and why these signs develop.
These signs represent a response that is programmed into your tissue. This response is one of your body's principal defense reactions, designed to anticipate, intercept and destroy invading microorganisms. Inflammation is best appreciated by understanding your body's functioning at the level of cells and tissues. Subsequent processes of tissue repair (healing) involve cell growth and division, cell movement and differentiation, and manufacture of extracellular material.
We go through life separated from our environment by a cellular boundary. This boundary -- including the epidermis of our skin and the epithelia of our various mucous membranes -- covers all our body's surfaces, even the internal surfaces of lungs, gut and glandular ducts. Nothing enters or leaves the body except by passing through or between the cells which form this epithelial boundary.
Whenever this epithelial boundary is broken, as it often is by scrapes and cuts and insect bites, two unfortunate things can happen. Good stuff like blood can leak out. And bad stuff like germs (microorganisms) can creep in. Plugging the leak can be fairly straightforward, with a quick patch (a blood clot) preventing significant loss of bodily substance. But a quick patch is not enough to prevent serious infection. Because germs are alive, they can grow and proliferate. So even a few microbes invading your body at the moment of injury could, if left unmolested, rapidly convert your warm, moist, well-oxygenated tissues into a thriving bacterial culture. Inflammation helps avoid this result.
Unfortunately, inflammation is uncomfortable. And inflammation can sometimes be triggered inappropriately (e.g., by allergies or autoimmune diseases). Many common medical treatments (e.g., aspirin and other "anti-inflammatory agents") are intended to relieve the discomfort and/or reduce the attendant tissue disturbance that inflammation may cause.
Any tissue or organ can become inflamed. Inflammation of a particular body part is named according to the site, with the "-itis" suffix appended (e.g., tonsillitis, appendicitis, dermatitis, arthritis, sinusitis, etc.). Thus many disease names are really just words that identify sites of inflammation.
Tissue repair. Following inflammation, injured tissue is usually replaced by new cells and extracellular materials, with undamaged surrounding cells proliferating and migrating to fill the void. Although some tissues, especially surface epithelium, can grow back quite efficiently, complex organization is seldom matched in the regenerated site. Gaps are quickly filled by collagen fibers produced by proliferating fibroblasts. A mass of collagen which replaces tissue that has been destroyed is known as a scar. Scars in the skin appear white because collagen is colorless, and healing often creates a more compact arrangement of collagen with fewer capillaries than the surrounding tissue. Scars in other organs also exist as firm masses of collagen in which normal organ function cannot occur. For example, cirrhosis of the liver represents extensive replacement by collagen of damaged liver cells.
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CARDINAL SIGNS OF INFLAMMATION
The four cardinal signs of inflammation -- the four "ORs"
- Rubor -- redness.
- Tumor -- swelling (puffiness, edema).
- Calor -- heat.
- Dolor -- pain.
(A fifth sign, loss of function, is sometimes included in this list.)
Where do these signs come from? What is happening to your body during inflammation? As you understand inflammation, you should be able to answer the following specific questions.
- Why does tissue become red and warm around a site of injury?
- Why does inflamed tissue swell?
- What is pus, and how does it form?
- How does healing occur?
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PHYSIOLOGY OF INFLAMMATION
The four cardinal signs of inflammation are readily explained by the behavior of the underlying cells and tissues. The inflammatory response consists of several physiological processes, all of which are triggered by the release of pharmacologically active substances such as histamine and heparin. These triggers of acute inflammation are released by mast cells, sensitive cells which are scattered throughout ordinary connective tissues and which react to tissue damage or other disturbance.
Chronic inflammation is maintained by more complex interactions among several cell types.
The basic components of the inflammatory response (see Webpath) are:
Vasodilation (increased vascular perfusion).
- Relaxation of the smooth muscle which surrounds terminal arterioles results in increased blood flow into the connective tissue capillary bed.
- Increased tissue perfusion in turn causes redness (rubor), as more red blood cells pass through the tissue, and warmth (calor), as blood carries body heat from the body's core to cooler peripheral tissues.
Increased vascular permeability (see Webpath).
- The endothelial lining of capillaries (endo = inside; the endothelium is the layer of thin, flat cells which line blood vessels) becomes more leaky, allowing more fluid (blood plasma) to exude into the connective tissue spaces.
- There is normally a balance between fluid leaving vascular spaces and fluid re-entering the system. Inflammation shifts this balance, causing accumulation of interstitial fluid.
- The fluid build-up which follows this permeability change is called edema and is visible as puffiness or swelling (tumor).
Note that edema can take a variety of forms, from mild (e.g., a blister) to life-threatening.
Emigration of leukocytes (see Webpath).
- Vasodilation and increased vascular perfusion are designed to prepare the way for the inflammatory infiltrate to enter the inflamed tissue.
- A combination of vasodilation with thickening of the blood (due to fluid leaking out of the vessels) causes a slowing of flow rate, which encourages leukocytes (white blood cells; leuko = white, cyte = cell) to stick to the sides of the vessels. This is called "margination" or "pavementing" (the white blood cells gather along the endothelium, like bricks paving a road).
- From here the leukocytes crawl between the endothelial cells and enter the inflamed connective tissue. Increased metabolic activity associated with leukocyte activity also generates heat (calor), contributing to local warmth.
Pain and/or itching (dolor) is caused by direct action on nerve endings of the chemical agents released during inflammation.
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INFLAMMATORY INFILTRATE (Introduction to inflammation)
The inflammatory or leukocytic infiltrate consists of white blood cells which leave the blood and enter (infiltrate) the inflamed connective tissue
- Images of inflammatory infiltrate in skin.
- Inflammatory infiltrate in salivary gland, from Webpath.
- Inflammatory infiltrate in nasal mucosa, from Webpath.
Cells of the inflammatory infiltrate include neutrophils, lymphocytes and monocytes. Immigration of these cells into peripheral tissues is one of the principal purposes for inflammation, bringing to a site of injury the immune-system cells which can combat infection and clean up damaged tissue.
Neutrophils (neutrophilic leukocytes) are the first white blood cells to enter the tissue during acute inflammation (see Webpath). Neutrophils are anti-bacterial cells which lyse (break down) bacterial cells by releasing lysosomal enzymes. Neutrophils recognize bacteria as foreign by the antibody molecules which have attached to the bacterial surface. Antibody molecules (molecules which bind to one specific antigen or foreign substance which the body has previously encountered) are found in blood plasma and interstitial fluid.
Neutrophils are the most numerous of the leukocytes, about 60% of the white blood cell count. They are about 12 Ám in diameter in blood smear preparations (about twice the size of red blood cells), and are polymorphonuclear (meaning their nuclei have a variable shape with several lobes; neutrophils are also called PMNs or polys, short for polymorphonuclear neutrophilic leukocytes). The cytoplasm contains many lysosomal granules (vesicles storing lysosomal enzymes) whose specific staining properties give these cells their name. The granules are neutrophilic, meaning they do not show a special affinity for either acidic or basic stains, but are stained mildly by both. This is in contrast to the specific granules of eosinophils, which stain red with eosin, and basophils, which stain with basic stains. Severe inflammation may increase the numbers of neutrophils in blood, resulting in neutrophilia
Neutrophils are only occasionally seen in tissue sections outside blood (except, of course, in inflamed tissue). Here they may be most easily recognized by their lobed nuclei. One neutrophil nucleus might be mistaken for a cluster of very small nuclei, but each of the lobes is much smaller than any whole nucleus--only two or three Ám across, much smaller than the nuclei of lymphocytes which are among the smallest of our cells.
[More on blood cells.]
Lymphocytes accumulate somewhat later during the inflammatory process. Their presence in large numbers indicates the continuing presence of antigen and thus may suggest an established infection. Lymphocytes produce the multitude of diverse antibody molecules (one specific type of antibody per lymphocyte) which provide the mechanism for chemical recognition of foreign materials (distinguishing between self and non-self) and so for mediating and regulating immune responses.
Lymphocytes travel in the blood, but they routinely leave capillaries and wander through connective tissue. Therefore, lymphocytes may be normally encountered at any time in any location. They even enter epithelial tissue, crawling between the epithelial cells. They reenter circulation via lymphatic system channels (hence their name). Lymph channels drain into lymph nodes, where dense aggregations of lymphocytes form lymph nodules. Each lymph nodule has a "germinal center", where activated lymphocytes proliferate. Lymph nodules with proliferating lymphocytes also characterize the tonsils and the appendix and may be encountered in other sites as well.
Research suggests that some types of lymphocytes are compartmentalized to particular tissues or body regions.
Lymphocytes are small cells, 7-9 Ám in diameter in blood smears, and are the second most common white blood cell type (about 30% of the WBCs). Each lymphocyte has a round heterochromatic (deeply staining) nucleus surrounded by a relatively thin rim of cytoplasm. Lymphocytes are most easily recognized in histological sections as small "naked" nuclei (the cytoplasm is usually inconspicuous) which occur here and there in most ordinary connective tissues. They are encountered most commonly near mucous membranes. Lymphocytes are found densely packed in lymphoid tissue, such as tonsils, spleen, and lymph nodes.
Plasma cells are lymphocytes which are specialized for mass production and secretion of circulating antibodies. Plasma cells have more extensive cytoplasm filled with rough endoplasmic reticulum (for synthesizing protein, specifically antibody molecules). This cytoplasm is distinctly basophilic, a consequence of the large numbers of ribosomes associated with the rER, and typically forms a lopsided bulge on one side of the nucleus. The heterochromatin of plasma cells is typically clumped in a characteristic "spoke-wheel" arrangement which also aids plasma cell recognition.
[More on blood cells.]
Monocytes are phagocytic cells which circulate in the blood. An equivalent cell type, called the macrophage, is a resident cell in connective tissue.
Monocytes/macrophages engulf and digest foreign microorganisms, dead or worn-out cells, and other tissue debris. They interact closely with lymphocytes to recognize and destroy foreign substances.
Resident macrophages normally remain at rest (rather than circulating in and out of tissues like the lymphocytes). But the normal number of fixed macrophages is supplemented during inflammation by the influx of many monocytes from the blood. When faced with a target too big for one cell, a splinter for example, several macrophages may fuse together to form a single huge multinucleate mass called a "foreign body giant cell."
Monocytes are the largest of the leukocytes, and constitute about 5% of the white blood cell population. In blood smears, monocyte nuclei are typically indented, with a kidney-bean shape. Tissue macrophages are diverse in appearance and not easily distinguished from the more common fibroblasts. Macrophages are generally larger, and may contain brown pigment granules which represent indigestible residue in tertiary lysosomes. In electron micrographs macrophages are generally recognized by the presence of numerous lysosomes of various sizes, including large heterophagic vesicles.
[More on blood cells.]
For more about the immune system, see CRR Lymphatic System. However, an in-depth treatment of the immune system is beyond the scope of this website.
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RECENT RESEARCH on inflammation
A special issue of Science (26 November 2021) includes several reviews of recent research on inflammation:
- "The spectrum of inflammatory responses" (vol. 374, p. 1070).
- "Dying cells fan the flames of inflammation" (vol. 374, p. 1076).
- "Mechanisms of viral inflammation and disease in humans" (vol. 374, p. 1080).
- "Signaling inflammation across the gut-brain axis" (vol. 374, p. 1087).
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SIUC / School
of Medicine / Anatomy / David
Last updated: 7 June 2022 / dgk