Outcomes of Acute and Chronic Inflammation PDF

23 OUTCOMES OF ACUTE INFLAMMATION AND CHRONIC INFLAMMATION ILOs By the end of this lecture, students will be able to Delineate outcomes of acute inflammation. Evaluate factors that transform an acute inflammation into and chronic one.Relate specific and non-specific chronic inflammation to e...

23 OUTCOMES OF ACUTE INFLAMMATION AND CHRONIC INFLAMMATION ILOs By the end of this lecture, students will be able to Delineate outcomes of acute inflammation. Evaluate factors that transform an acute inflammation into and chronic one.Relate specific and non-specific chronic inflammation to etiology, pathogenesis, chemical mediators and acting cells Interpret non-specific chronic inflammation and granulomatous reaction in relation to corresponding clinical situations Understand the underlying pathogenesis of the systemic effects of inflammation. Outcomes of Acute Inflammation Factors affecting the outcome of acute inflammation: The nature of injury The intensity of injury The tissue involved Host responsiveness Generally acute inflammation has one of three outcomes: • Complete resolution: Resolution means restoration of the site of acute inflammation to normal. It involves removal of cellular debris and microbes by macrophages, and resorption of edema fluid by lymphatics. It is the usual outcome when: The injury is limited or short-lived. E.g: Common cold. There has been little tissue destruction. E.g: Small skin blisters. The damaged parenchymal cells can regenerate. E.g: bone after a fracture or epithelium after a superficial skin wound). Such regeneration can occur through the proliferation of adjacent surviving cells or through the activity of tissue stem cells. • Healing by connective tissue replacement (fibrosis): This occurs when: There is substantial tissue destruction. Example: suppurative inflammation. Purulent pericarditis usually heals by fibrosis resulting in constrictive pericarditis or adhesive pericarditis. The inflammatory injury involves tissues that are incapable of regeneration. Example: Burns involving a large area of the body. There is abundant fibrin exudation in tissue or in serous cavities (pleura, peritoneum) that cannot be adequately cleared. The process of resolution of inflammatory exudates by fibrosis is called: organization. E.g: Some cases of fibrinous pericarditis in which excess fibrin is not removed. In all these situations, connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous tissue. • Progression to chronic inflammation: Acute to chronic transition occurs when the acute inflammatory response cannot be resolved, as a result of either: The persistence of the injurious agent. Example: Hepatitis C viral infection usually progresses to chronic inflammation due to persistence of viral particles in hepatocytes. Some interference with the normal process of healing. Example: Diabetic ulcers. Chronic Inflammation Chronic inflammation is a prolonged process (weeks or months) in which active inflammation, tissue destruction, and healing all proceed simultaneously. It occurs in the following contexts: After acute inflammation, as part of the normal healing process. Due to persistence of an inciting stimulus or repeated bouts of acute inflammation. As a low-grade( hidden reaction) without prior acute inflammation. Causes of Chronic Inflammation Persistent infection by intracellular microbes (e.g., tubercle bacilli, viruses) of low direct toxicity but nevertheless capable of evoking immunologic responses Hypersensitivity diseases, particularly reactions directed against self (e.g., autoimmune diseases) or abnormally regulated responses to normal host flora (inflammatory bowel disease) or benign environmental substances (allergy). Prolonged exposure to potentially toxic exogenous (e.g., silica, causing pulmonary silicosis) or endogenous substances (e.g., lipids, causing atherosclerosis) Diseases not conventionally considered inflammatory (e.g., neurodegenerative disorders [Alzheimer disease], metabolic syndrome, and cancers potentially driven by inflammation) Morphological features Infiltration with mononuclear inflammatory cells, including macrophages, lymphocytes, and plasma cells Tissue destruction, induced by persistent injury and/or inflammation Attempts at healing by connective tissue replacement, accomplished by vascular proliferation (angiogenesis) and fibrosis Types of chronic inflammation: Chronic non-specific inflammation. Granulomatous inflammation. Granulomatous Inflammation It is a distinctive form of chronic inflammation is characterized by focal accumulations of activated macrophages (granulomas); macrophage activation is reflected by enlargement and flattening of the cells (so-called epithelioid macrophages). • Nodules of epithelioid macrophages in granulomatous inflammation are surrounded by a collar of lymphocytes elaborating factors necessary to induce macrophage activation. Activated macrophages may fuse to form multinucleated giant cells, and central necrosis may be present in some granulomas (particularly from infectious causes). Older granulomas can be surrounded by a rim of fibrosis. Causes of granulomatous inflammation: Infectious etiologies: Tuberculosis, leprosy, syphilis, cat-scratch disease, schistosomiasis, certain fungal infections Inflammatory causes: Temporal arteritis, Crohn disease, sarcoidosis Inorganic particulates: Silicosis, berylliosis Types of granulomas include: Foreign body granulomas are incited by particles that cannot be readily phagocytosed by a single macrophage but do not elicit a specific immune response (e.g., suture or talc). Immune granulomas are formed by immune T cell-mediated responses to persistent, poorly degradable antigens. IFN-γ from activated T cells causes the macrophage transformation to epithelioid cells and the formation of multinucleated giant cells. The prototypical immune granuloma is caused by the tuberculosis bacillus; in that setting the granuloma is called a tubercle and classically exhibits central caseous necrosis. Systemic Effects of Inflammation Systemic changes associated with inflammation are collectively called the acute phase response or—in severe cases—the systemic inflammatory response syndrome (SIRS). These represent responses to cytokines produced either by bacterial products (e.g., endotoxin) or by other inflammatory stimuli. The acute phase response consists of several clinical and pathologic changes: Fever: Temperature elevation (1 to 4° C) occurs in response to pyrogens—substances that stimulate prostaglandin synthesis in the hypothalamus. For example, endotoxin stimulates leukocyte release of IL-1 and TNF that increase COX production of prostaglandins. In the hypothalamus, PGE2 resets the temperature set point. Aspirin reduces fever by inhibiting COX activity to block PG synthesis. Acute-phase proteins: are plasma proteins mostly of hepatic origin; their synthesis increases several hundred-fold in response to inflammatory stimuli (e.g., cytokines, such as IL-6 and TNF). These include C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein. CRP and SAA bind to microbial cell walls, acting as opsonins and fixing complement. They also help to clear necrotic cell nuclei and mobilize metabolic stores. Elevated fibrinogen leads to increased erythrocyte aggregation (increasing the erythrocyte sedimentation rate on ex vivo testing). Hepcidin is another acute-phase reactant responsible for regulating release of intracellular iron stores; chronically elevated hepcidin is responsible for the iron-deficiency anemia associated with chronic inflammation. Leukocytosis (increased white cell number in peripheral blood) is common in inflammatory reactions; there is an accelerated release of bone marrow cells, typically with immature neutrophils in the blood (so-called shift to the left). Prolonged infection also induces proliferation of bone marrow precursors due to increased colony-stimulating factor (CSF) production. The leukocyte count usually climbs to 15,000 to 20,000 cells/μL. Bacterial infections typically increase neutrophil numbers (neutrophilia) Viral infections increase lymphocyte numbers (lymphocytosis) Parasitic infestations and allergic disorders are associated with increased eosinophils (eosinophilia) Certain infections (typhoid fever, rickettsiae, and some viruses and protozoans) are associated with decreased circulating white cell numbers due to increased consumption (leukopenia). Other manifestations of the acute phase response due to cytokine effects on the central nervous system (CNS) include: Increased pulse and blood pressure; Decreased sweating (due to blood flow diverted from cutaneous to deep vascular beds to limit heat loss) Rigors (shivering) and chills Anorexia, somnolence, and malaise. In sepsis, organisms and/or endotoxin can stimulate the production of enormous quantities of several cytokines, notably TNF and IL-1. High levels of these cytokines result in a clinical triad of disseminated intravascular coagulation (DIC), metabolic disturbances, and cardiovascular failure described as septic shock. References: Kumar, Abbas, Aster. Robbins Basic Pathology, 10th ed. Elsevier. Mitchell, Kumar, Abbas, Aster. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease, 9th ed. Elsevier.