Inflammation Lecture Notes PDF

Clinical photograph The conjunctiva was hyperemic, swollen, and purulent Y Suyama, R Akiyama. N Engl J Med 2022;386:e46. Lecture 3: Objectives 1. Describe the overview of inflammation and its general features. 2. Correlate the cardinal signs of inflammation with pathophysiologic events that characte...

Clinical photograph The conjunctiva was hyperemic, swollen, and purulent Y Suyama, R Akiyama. N Engl J Med 2022;386:e46. Lecture 3: Objectives 1. Describe the overview of inflammation and its general features. 2. Correlate the cardinal signs of inflammation with pathophysiologic events that characterize acute inflammation. 3. Distinguish between the inflammatory cells of acute and chronic Inflammation. 4. Describe the causes of inflammation and recognition of microbes and damaged cells. 5. Describe the reaction of blood vessels in acute inflammation, (vascular flow & caliber changes, vascular leakage, responses of lymphatics & edema) 6. Briefly describe leukocyte recruitment at site of inflammation- adhesion, migration, and chemotaxis 7. Distinguish between the types of Interstitial fluids “Exudate vs Transudate” 8. Describe phagocytosis recognition, engulfment and intracellular destruction of microbes, debris (Reactive Oxygen Species, Nitric Oxide, Enzymes and Neutrophil Extracellular Traps) and the role of the complement system. 9. Describe the leukocyte-mediated tissue injury and the termination of the acute inflammatory response. Objective 1 Describe the overview of inflammation and its features Inflammation: definitions and clinical features Definition Systemic and local reaction of tissues and microcirculation to a pathogenic insult Allows inflammatory cells, plasma proteins, and fluid to exit blood vessels and enter the interstitial space Divided into acute and chronic inflammation Inflammation: definitions and clinical features Acute inflammation Acute inflammation Arises in response to infections ( to eliminate pathogen) or tissue necrosis ( to clear necrotic debris) Presence of edema and neutrophils in tissues Objective 2 Correlate the cardinal signs of inflammation with pathophysiologic events that characterize acute inflammation Acute inflammation: cardinal signs Redness (rubor) and warmth (calor) Due to vasodilation which ↑ blood flow Occurs via relaxation of arteriolar smooth muscle Key mediators histamine, prostaglandins, and bradykinin Swelling (tumor) Due to leakage of fluid from postcapillary venules into the interstitial space (exudate) Key mediators Histamine which causes endothelial cell contraction tissue damage → endothelial cell disruption Acute inflammation: cardinal signs Edema ↑blood flow to the injured area and increased vascular permeability leading to the accumulation of extravascular fluid rich in plasma proteins Pain (dolor) Releasing of prostaglandins, neuropeptides, and cytokines Bradykinin and PGE2 sensitize sensory nerve endings Acute inflammation: cardinal signs loss of function ( functio laesa) Leukocytes that are recruited and activated by the offending agent and by endogenous mediators release toxic metabolites and proteases extracellularly Fever Pyrogens (e.g., LPS from bacteria) cause macrophages to release IL-1, IL-6, and TNF, which↑ cyclooxygenase activity in perivascular cells of the hypothalamus Outcomes of Acute Inflammation Resolution and healing Anti-inflammatory cytokines (e.g., IL-10 and TGF-B) Continued acute Inflammation Persistent pus formation IL-8 from macrophages recruits additional neutrophils Abscess formation Acute inflammation surrounded by fibrosis Macrophages mediate fibrosis via fibrogenic growth factors and cytokines Chronic inflammation Macrophages present antigens to activate CD4+ helper T cells, which secrete cytokines that promote inflammation Objective # 3 Distinguish between the inflammatory cells of acute and chronic Inflammation Cells of acute inflammation: morphology and function Neutrophils Most prominent inflammatory cells in foci of acute inflammation during the first 24 hours Neutrophilia Increased neutrophils in the peripheral blood Common etiology Bacterial infections Infarction Cells of acute inflammation: morphology and function Normal neutrophil nuclear segmentation and normal granulation of the cytoplasm are evident in this circulating neutrophil. Neutrophils typically have 3-5 nuclear lobes with a thin strand of chromatin connecting these lobes. The cytoplasm has a pinkish tint from secondary granules Cells of acute inflammation: morphology and function Neutrophilia Neutrophilia is the most common finding in persons presenting with acute bacterial, some viral, and rare fungal infections. Densely packed polymorphonuclear leukocytes (PMNs) with multilobed nuclei Cells of acute inflammation: morphology and function Neutrophils: most prominent during the first 24 hours A B Chronic inflammation: definition Definition Outcome of acute inflammation when the inciting injury is persistent or recurrent or when the inflammatory reaction is insufficient to completely degrade the agent Delayed response, but more specific (adaptive immunity) that acute inflammation Cells Lymphocytes and plasma cells in tissue Cells of chronic inflammation: morphology and function Lymphocytes Lymphocytes Most prominent inflammatory cells in many viral infections Along with monocytes–macrophages and plasma cells, are the most prominent cells in chronic inflammation Lymphocytosis (i.e., an increased number of lymphocytes in the peripheral blood) Cells of chronic inflammation: morphology and function Lymphocytes This peripheral blood smear from a normal adult female shows uniform erythrocytes with a normal central pallor, normal platelets, and a nonactivated lymphocyte There is some variation in platelet size (black curved arrow), but all platelets are well-granulated Cells of inflammation: morphology and function Lymphocytes Lymphocytes may be seen in a variety of viral infections. Infectious mononucleosis must be considered in a young person with lymphocytosis and marked lymphocyte heterogeneity Cells of chronic inflammation: morphology and function Monocytes - Macrophages Monocytes–macrophages After 2–3 days, neutrophils are replaced mainly by monocytes– macrophages, which are capable of engulfing larger particles, are longer lived and are capable of dividing and proliferating within the inflamed tissue Monocytosis (i.e., increased number of monocytes in the peripheral blood) Cells of inflammation: morphology and function monocytes and macrophages A monocyte is characterized by a large size, blue-gray cytoplasm with occasional granules and vacuoles, and a somewhat folded nucleus. The nuclear chromatin has a "hills and valleys" appearance Cells of inflammation: morphology and function monocytes and macrophages Lymphocytes (double-headed arrow), plasma cells (arrows) and a few macrophages (arrowheads) are present Cells of inflammation: morphology and function Eosinophils, mast cells, basophils Eosinophils Predominant inflammatory cells in allergic reactions and parasitic infestations Mast cells and basophils They are sources of histamine Important causes of basophilia include chronic myelogenous leukemia and other myeloproliferative diseases Cells of inflammation: morphology and function Review question # 1 1. A 72-year-old male presents with a 3-day history of progressively worsening productive cough, fever, chills, and signs of toxicity. Prominent physical findings include signs of consolidation and rales over the right lung base. Sputum culture is positive for Streptococcus pneumoniae. An intra-alveolar exudate filling the alveoli of the involved portion of the lung is present. Which of the following types of inflammatory cells is most likely a prominent feature of this exudate? A. Basophils B. Eosinophils C. Lymphocytes D. Monocytes-macrophages E. Neutrophils Cells of inflammation: morphology and function Review question # 2 2. A routine complete blood count performed on a 22-year-old medical student reveals an abnormality in the differential leukocyte count. She has been complaining of frequent sneezing and “watery” eyes during the past several weeks and reports that she frequently had such episodes in the spring and summer. Which of the following cell types is most likely to be increased? A. Basophils B. Eosinophils C. Lymphocytes D. Monocytes E. Neutrophils Objective # 4 Describe the causes of inflammation and recognition of microbes and damaged cells Causes of Inflammation Type of Leukocytosis Causes Neutrophilic leukocytosis Acute bacterial infections, especially those caused by pyogenic organisms; sterile inflammation caused by, for example, tissue necrosis (myocardial infarction, burns) Eosinophilic leukocytosis (eosinophilia) Allergic disorders such as asthma, hay fever, parasitic infestations; drug reactions; certain malignancies (e.g., Hodgkin and some non-Hodgkin lymphomas); autoimmune disorders (e.g., pemphigus, dermatitis herpetiformis) and some vasculitides; atheroembolic disease (transient) Basophilic leukocytosis (basophilia) Rare, often indicative of a myeloproliferative neoplasm (e.g., chronic myeloid leukemia) Causes of Inflammation Type of Leukocytosis Monocytosis Causes Chronic infections (e.g., tuberculosis), bacterial endocarditis, rickettsiosis, and malaria; autoimmune disorders (e.g., systemic lupus erythematosus); inflammatory bowel diseases (e.g., ulcerative colitis) Lymphocytosis Accompanies monocytosis in many disorders associated with chronic immunologic stimulation (e.g., tuberculosis, brucellosis); viral infections (e.g., hepatitis A, cytomegalovirus, Epstein-Barr virus); Bordetella pertussis infectio Objective # 5 Describe the reaction of blood vessels in acute inflammation, (vascular flow & caliber changes, vascular leakage, responses of lymphatics & edema) Objective # 7 Distinguish between the types of Interstitial fluids “Exudate vs Transudate” Sequence of events in an inflammatory reaction reaction of blood vessels in acute inflammation Vascular reactions Changes in the flow of blood Permeability of vessels Why changes in the flow of blood? Movement of plasma proteins and leukocytes out of the circulation and into the site of infection or injury Exudation The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities Exudate Extravascular fluid that has a high protein concentration and contains cellular debris Its presence implies the existence of an inflammatory process that has increased the permeability of small blood vessels reaction of blood vessels in acute inflammation Changes in the flow of blood: definitions Transudate Fluid with ↓protein content (most of which is albumin), li le or no cellular material, and low specific gravity ultrafiltrate of blood plasma that is produced as a result of osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability Edema Excess of fluid in the interstitial tissue or serous cavities it can be either an exudate or a transudate Pus, a purulent exudate, is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells, and, in many cases, microbes Serous pleural effusion A transudate or serous pleural effusion is clear yellow. It is translucent and optically inverts. Transudates are usually signs of cardiac or circulatory disease, not primary lung disease Formation of exudates and transudates Increased Vascular Permeability (Vascular Leakage) Several mechanisms are responsible for the increased permeability of postcapillary venules, a hallmark of acute inflammation Increased Vascular Permeability (Vascular Leakage) Principal mechanisms of increased vascular permeability in inflammation and their features and underlying cause Responses of Lymphatic Vessels and Lymph Nodes Healthy state The system of lymphatics and lymph nodes filters and polices the extravascular fluids Lymphatics drain the small amount of extravascular fluid that seeps out of capillaries Inflammation Lymph flow is increased and helps drain edema fluid that accumulates because of increased vascular permeability Responses of Lymphatic Vessels and Lymph Nodes In addition to fluid, leukocytes and cell debris, as well as microbes, may find their way into lymph Lymphatic vessels, like blood vessels, proliferate during inflammatory reactions to handle the increased load. The lymphatics may become secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis). Inflamed lymph nodes are often enlarged because of hyperplasia of the lymphoid follicles and increased numbers of lymphocytes and macrophages. This constellation of pathologic changes is termed reactive, or inflammatory, lymphadenitis Objective 6 Briefly describe leukocyte recruitment at site of inflammation- adhesion, migration, and chemotaxis leukocyte recruitment: journey of leukocytes from the vessel lumen to the tissue In the lumen Margination exit from the center of the bloodstream into the peripheral part Rolling Adhesion to endothelium Transmigration Migration across the endothelium and vessel wall Migration in the tissues toward a chemotactic stimulus→ Chemotaxis Review Question # 3 “Rolling of leucocytes” 3: A 6-year-old child has a history of recurrent infections with pyogenic bacteria, including Staphylococcus aureus and Streptococcus pneumoniae. The infections are accompanied by a neutrophilic leukocytosis. Microscopic examination of a biopsy specimen obtained from an area of soft tissue necrosis shows microbial organisms, but very few neutrophils. An analysis of neutrophil function shows a defect in rolling. This child’s increased susceptibility to infection is most likely caused by a defect involving which of the following molecules? A. Complement C3b B. Integrins C. Leukotriene B4 D. NADPH oxidase E. Selectins Answer to review Question # 3 Correct answer E: “Selectins” Leukocyte rolling is the first step in transmigration of neutrophils from the vasculature to the tissues Rolling depends on interaction between selectins Endothelial cells P-selectin and E-selectin Neutrophils L-selectin and their sialylated ligands (e.g., sialylated Lewis X) Answer to review Question # 3 Other options Option B: Integrins are involved in the next step of transmigration, during which there is firm adhesion between neutrophils and endothelial cells. Option A: Complement C3b acts as an opsonin to facilitate phagocytosis. Option C: Leukotriene B4 is a chemotactic agent. Option D: NADPH oxidase is involved in phagocytic cell microbicidal activity Review question # 4 “Chemotaxis” 3. A laboratory experiment is performed to evaluate the chemotactic potential of a group of potential mediators. Which of the following substances most likely has the greatest affinity for neutrophils? A. C5a B. Fucosyltransferase C. β2-Integrin D. P-selectin E. TNF-α Acute inflammation: chemotactic factors General considerations Exogenous and endogenous substances Bacterial products Cytokines, especially those of the chemokine family Components of the complement system, particularly C5a Products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly leukotriene B4 (LTB4) Chemotactic factors Factor Description Chemotactic For Formylated peptides Bacterial products of Escherichia coli Neutrophils C5a Activated complement component Neutrophils HETE, LTB4 Leukotrienes Neutrophils Kallikrein Product of factor XIIa–mediated conversion of prekallikrein Neutrophils Fibrinogen Plasma protein Neutrophils PAF AGEPC; from basophils, mast cells, and other cells Eosinophils PDGF From platelets, monocytesmacrophages, smooth muscle cells, and endothelial cells Neutrophils and macrophages TGF-β From platelets, neutrophils, macrophages, lymphocytes, and fibroblasts Macrophages and fibroblasts Fibronectin Extracellular matrix protein Fibroblasts and endothelial cells Objective # 8 Describe phagocytosis recognition, engulfment and intracellular destruction of microbes, debris (Reactive Oxygen Species, Nitric Oxide, Enzymes and Neutrophil Extracellular Traps) and the role of the complement system Phagocytosis and Clearance of the Offending Agent The two major phagocytes are neutrophils and macrophages Review question # 5 5: A 12-month-old boy with a 6-month history of repeated infections has had a fever and cough for the past 3 days. A Gram stain of sputum shows many gram-positive cocci in chains. CBC shows neutrophilia. Laboratory studies show that the patient’s neutrophils phagocytose and kill organisms promptly in the presence of normal human serum, but not in his own serum. The neutrophils migrate normally in a chemotaxis assay. Which of the following is the most likely cause of this boy’s increased susceptibility to infection? A. Abnormality of selectin expression B. Diminished opsonization C. Defective neutrophil generation of hydrogen peroxide D. Deficiency of integrins E. Phagocytic cell microtubular protein defect Review question # 5 Correct answer B: This immunoglobulin deficiency prevents opsonization and phagocytosis of microbes. Deficiency of integrins and selectins, or a defect in microtubules, would prevent adhesion and locomotion of neutrophils. H2O2 production is part of the oxygen-dependent killing mechanism. This mechanism is intact in this patient because the neutrophils are able to kill bacteria when immunoglobulins in normal serum allow phagocytosis Phagocytosis and Clearance of the Offending Agent Opsonization Opsonization It is the coating of particulate material by substances referred to as opsonins, which immobilize the particles on the surface of the phagocyte Most important opsonins IgG subtypes and C3b, a complement component IgG Fragments opsonized by IgG are bound to phagocytic cells by cell-surface receptors for the Fc portion of the IgG molecule C3b Fragments opsonized by C3b bind to cellular receptors for C3b Phagocytosis and Clearance of the Offending Agent Oxygen-dependent microbial killing Outcomes of Acute Inflammation