The Nature of Disease Pathology for the Health Professions Thomas H. McConnell Chapter 2 Cellular Pathology: Injury, Inflammation, and Repair Inflammation

Chapter 2: Cell Injury, Disease, and Death The Inflammatory Response to Injury Can be acute or chronic Cells of Inflammation Granulocytes -> neutrophils, basophils, eosinophils Agranulocytes -> monocytes, lymphocytes Platelets (hemostasis) Chemicals of Inflammation Cell Derived Plasma Derived Inflammatory Response -> vascular first, then cellular Vascular response -> arteriolar vasoconstriction followed by vasodilation Hyperemia – capillaries flooded with blood, causes edema Edema – plasma leaks into tissues Cellular response Cells leave blood via diapedesis Attracted to area by chemotaxis

The Inflammatory Response to Injury The initial inflammatory response is vascular Chemical signals mediate the inflammatory process Cellular reaction follows vascular reaction - Leukocytes are the cells of inflammation - Inflammation has effects beyond the site of injury - Acute inflammation follows brief injury - Chronic inflammation occurs with persistent injury *See Animation on thePoint Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

Components/Characteristics of Inflammation Purpose of Inflammation: - Limit effect of injury Neutralize offending stimulus Initiate the repair process Action of inflammatory mediators Characteristics of Inflammation: - Tumor (swelling) - Calor (heat) - Dolor (pain) - Rubor (redness) - Functio Laesa (loss of function) Figures from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

Chapter 2: Cell Injury, Disease, and Death Acute Inflammation Follows a brief injury Lasts only a few hours to a few days Usually resolved without scarring Phases after injury Immediate vasoconstriction Vasodilation Vascular wall changes Migration of neutrophils Accumulation of exudates Characteristics Observable: swelling, redness, heat, and pain Microscopic: injured cells, dilated capillaries, accumulation of neutrophils Accumulation of fluids and cells = acute inflammatory exudate Serous: watery, few cells, little protein Fibrinous: thicker, more cells, fibrin Suppurative: liquefactive necrosis with pus

Sequence of Events in Acute Inflammation Acute Inflammatory Response: Note that vascular events (hyperemia, edema) come first, then cellular events, then exudates Figures from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

Acute Inflammatory Exudate Accumulation of fluid and WBCs at injury site Three major anatomic patterns: Serous inflammation Seen in mild, short-term inflammation Watery fluid with decreased protein No/few inflammatory cells Fibrinous inflammation Seen in more severe injuries Thicker, with coagulation factors (fibrin) Neutrophils Suppurative (purulent, pyogenic) inflammation Seen with severe injuries Associated with liquefactive necrosis; pus (dead cells/debris) Frequently associated with bacterial infection Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

Resolution of Acute Inflammation Most acute inflammation heals quickly unless an abscess is present or chronic inflammation develops Complete resolution Mild Injury Cells, debris, fluid cleared from site Scarring with severe or repeated acute inflammation Chronic inflammation may develop if cause of initial inflammation persists

Chapter 2: Cell Injury, Disease, and Death Chronic Inflammation Occurs with a persistent or repeated moderate injury, e.g., infection, autoimmune disease, persistent exposure to injurious agent Characteristics Less intense than acute inflammation Mixture of ongoing inflammation and repeated healing Immune response evoked: macrophages, lymphocytes Granulomatous inflammation unique type of chronic inflammation Macrophages aggregated around a necrotic focus Multinucleated giant cells are characteristic Microscopic: injured cells, dilated capillaries, accumulation of neutrophils Accumulation of fluids and cells = acute inflammatory exudate Serous: watery, few cells, little protein Fibrinous: thicker, more cells, fibrin Suppurative: liquefactive necrosis with pus

Chronic Inflammation Persistence of injurious agent is its hallmark Mixture of ongoing inflammation and healing Usual causes: Persistent infection Autoimmune disease Persistent exposure to injurious agents Characteristics Less intense than acute inflammation Usually hot, swollen, red, and tender Marked by lymphocytic infiltrate May result in granulomatous inflammation Granuloma[a] (plural granulomas or granulomata) is an inflammation found in many diseases. It is a collection of immune cells known as histiocytes.[1] Granulomas form when the immune system attempts to wall off substances it perceives as foreign but is unable to eliminate. Such substances include infectious organisms including bacteria and fungi, as well as other materials such as keratin and suture fragments.[1][2][3][4] The adjective granulomatous means characterized by granulomas. In pathology, a granuloma is an organized collection of macrophages.[1][5] In medical practice, doctors occasionally use the term "granuloma" loosely to mean "a small nodule". Since a small nodule can represent anything from a harmless nevus to a malignant tumor, this usage of the term is not very specific. Examples of the inaccurate use of the term granuloma are the lesions known as vocal cord granuloma, pyogenic granuloma and intubation granuloma, all of which are examples of granulation tissue, not granulomas. "Pulmonary hyalinizing granuloma" is a lesion characterized by keloid-like fibrosis in the lung, and is not granulomatous. Similarly, radiologists often use the term granuloma when they see a calcified nodule on X-ray or CT scan of the chest. They make this assumption since granulomas usually contain calcium, although the cells that form a granuloma are too tiny to be seen by a radiologist. The most accurate use of the term "granuloma" requires a pathologist to examine surgically removed and specially colored (stained) tissue under a microscope. Macrophages (also known as histiocytes) are the cells that define a granuloma. They often, but not invariably, fuse to form multinucleated giant cells (Langhans giant cell).[6] The macrophages in granulomas are often referred to as "epithelioid". This term refers to the vague resemblance of these macrophages to epithelial cells. Epithelioid macrophages differ from ordinary macrophages in that they have elongated nuclei that often resemble the sole of a slipper or shoe. They also have larger nuclei than ordinary macrophages and their cytoplasm is typically more pink when stained with eosin. These changes are thought to be a consequence of "activation" of the macrophage by the offending antigen. The other key term in the above definition is the word "organized" that refers to a tight, ball-like formation. The macrophages in these formations are typically so tightly clustered that the borders of individual cells are difficult to appreciate. Loosely dispersed macrophages are not considered to be granulomas. All granulomas, regardless of cause, may contain additional cells and matrix. These include lymphocytes, neutrophils, eosinophils, multinucleated giant cells, fibroblasts and collagen (fibrosis). The additional cells are sometimes a clue to the cause of the granuloma. For example, granulomas with numerous eosinophils may be a clue to coccidioidomycosis or allergic bronchopulmonary fungal disease, and granulomas with numerous neutrophils suggest blastomycosis, granulomatosis with polyangiitis, aspiration pneumonia orcat-scratch disease. In terms of the underlying cause, the difference between granulomas and other types of inflammation is that granulomas form in response to antigens that are resistant to "first-responder" inflammatory cells such as neutrophils and eosinophils. The antigen causing the formation of a granuloma is most often an infectious pathogen or a substance foreign to the body, but often the offending antigen is unknown (as in sarcoidosis). Granulomas are seen in a wide variety of diseases, both infectious and non-infectious.[1][2] Infections that are characterized by granulomas include tuberculosis, leprosy, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis and cat scratch disease. Examples of non-infectious granulomatous diseases are sarcoidosis, Crohn's disease, berylliosis, granulomatosis with polyangiitis, Churg-Strauss syndrome, pulmonary rheumatoid nodules and aspiration of food and other particulate material into the lung. An important feature of granulomas is whether or not they contain necrosis. Necrosis refers to dead cells that, under the microscope, appear as a mass of formless debris with no nuclei present. A related term, "caseation" (literally: turning to cheese) refers to a form of necrosis that, to the unaided eye (i.e., without a microscope), appears cheese-like ("caseous"), and is typically (but not uniquely) a feature of the granulomas of tuberculosis. The identification of necrosis in granulomas is important because granulomas with necrosis tend to have infectious causes.[1] There are several exceptions to this general rule, but it nevertheless remains useful in day-to-day diagnostic pathology. Figure from: McConnell, The Nature of Disease, 2nd ed., Wolters Kluwer, 2014

Non-local Effects of Inflammation Lymphatic System Lymphangitis (inflammation of lymph vessels) Lymphadenitis (infected lymph nodes) Lymphadenopathy (lymph node enlargement) Reactive hyperplasia (non-infected enlargement) Systemic Effects Inflammatory mediators enter blood In brain: fever, malaise, drowsiness, loss of appetite In liver: production of reactant proteins C-reactive protein – very reliable marker of inflammation Fibrinogen – Increased ESR Ann Med. 2000 May;32(4):274-8. Function of C-reactive protein. Du Clos TW1. Abstract C-reactive protein (CRP) is an ancient highly conserved molecule and a member of the pentraxin family of proteins. CRP is secreted by the liver in response to a variety of inflammatory cytokines. Levels of CRP increase very rapidly in response to trauma, inflammation, and infection and decrease just as rapidly with the resolution of the condition. Thus, the measurement of CRP is widely used to monitor various inflammatory states. CRP binds to damaged tissue, to nuclear antigens and to certain pathogenic organisms in a calcium-dependent manner. The function of CRP is felt to be related to its role in the innate immune system. Similar to immunoglobulin (Ig)G, it activates complement, binds to Fc receptors and acts as an opsonin for various pathogens. Interaction of CRP with Fc receptors leads to the generation of proinflammatory cytokines that enhance the inflammatory response. Unlike IgG, which specifically recognizes distinct antigenic epitopes, CRP recognizes altered self and foreign molecules based on pattern recognition. Thus, CRP is though to act as a surveillance molecule for altered self and certain pathogens. This recognition provides early defense and leads to a proinflammatory signal and activation of the humoural, adaptive immune system.