NS 521 - Inflammation <ul><li>Overview of Cellular Mechanisms Involved in Acute Inflammation </li></ul><ul><li>Chemical Mediators of Acute Inflammation </li></ul><ul><li>Examples of Acute Inflammatory Responses </li></ul><ul><li>Differences Between Acute and Chronic Inflammation </li></ul><ul><li>Examples of Chronic Inflammation </li></ul><ul><li>Discussion of Potential Roles of Nutrition in Inflammation </li></ul>
Acute Inflammation Acute inflammation is a rapid response to an injurious agent that serves to deliver mediators of host defense—leukocytes and plasma proteins—to the site of injury. Acute inflammation has three major components: (1) alterations in vascular caliber that lead to an increase in blood flow ; (2) structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation ; and (3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent
Acute inflammatory reactions are triggered by a variety of stimuli: • Infections (bacterial, viral, parasitic) and microbial toxins • Trauma (blunt and penetrating) • Physical and chemical agents (thermal injury, e.g., burns or frostbite; irradiation; some environmental chemicals) • Tissue necrosis (from any cause) • Foreign bodies (splinters, dirt, sutures) • Immune reactions (also called hypersensitivity reactions)
Acute Inflammation When a host encounters an injurious agent, such as an infectious microbe or dead cells, phagocytes that reside in all tissues try to get rid of these agents. At the same time, phagocytes and other host cells react to the presence of the foreign or abnormal substance by liberating cytokines, lipid messengers, and the various other mediators of inflammation. Some of these mediators act on endothelial cells in the vicinity and promote the efflux of plasma and the recruitment of circulating leukocytes to the site where the offending agent is located.
Acute Inflammation - continued As the injurious agent is eliminated and anti-inflammatory mechanisms become active, the process subsides and the host returns to a normal state of health. If the injurious agent cannot be quickly eliminated, the result may be chronic inflammation . The recruited leukocytes are activated by the injurious agent and by locally produced mediators, and the activated leukocytes try to remove the offending agent by phagocytosis.
The vascular phenomena of acute inflammation are characterized by increased blood flow to the injured area, resulting mainly from arteriolar dilation and opening of capillary beds induced by mediators such as histamine. Increased vascular permeability results in the accumulation of protein-rich extravascular fluid, which forms the exudate. Plasma proteins leave the vessels, most commonly through widened interendothelial cell junctions of the venules. The redness (rubor) , warmth (calor) , and swelling (tumor) of acute inflammation are caused by the increased blood flow and edema.
Circulating leukocytes, initially predominantly neutrophils, adhere to the endothelium via adhesion molecules, transmigrate across the endothelium, and migrate to the site of injury under the influence of chemotactic agents. Leukocytes that are activated by the offending agent and by endogenous mediators may release toxic metabolites and proteases extracellularly, causing tissue damage. During the damage, and in part as a result of the liberation of prostaglandins, neuropeptides, and cytokines, one of the local symptoms is pain ( dolor ).
Changes in vascular flow and caliber begin early after injury and develop at varying rates depending on the severity of the injury. The changes occur in the following order: • Vasodilation . Increased blood flow is the cause of the heat and the redness. Vasodilation is induced by the action of several mediators, notably histamine and nitric oxide on smooth muscle . • Increased permeability of the microvasculature . • Stasis . The loss of fluid results in concentration of red cells in small vessels and increased viscosity of the blood.
A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich fluid ( exudate ) into the extravascular tissue. The loss of protein from the plasma reduces the intravascular osmotic pressure and increases the osmotic pressure of the interstitial fluid. Together with the increased hydrostatic pressure owing to increased blood flow through the dilated vessels, this leads to a marked outflow of fluid and its accumulation in the interstitial tissue. The net increase of extravascular fluid results in edema .
Vascular Permeability – Leakage of Carbon Particles
EDEMA In acute inflammation, fluid loss from vessels with increased permeability occurs in distinct phases : (1) an immediate transient response lasting for 30 minutes or less, mediated mainly by the actions of histamine and leukotrienes on endothelium; (2) a delayed response starting at about 2 hours and lasting for about 8 hours, mediated by kinins, complement products, and other factors; and (3) a prolonged response that is most noticeable after direct endothelial injury, for example, after burns.
The sequence of events in the journey of leukocytes from the vessel lumen to the interstitial tissue, called extravasation , can be divided into the following steps : 1. In the lumen: margination , rolling , and adhesion to endothelium. Vascular endothelium normally does not bind circulating cells or impede their passage. In inflammation, the endothelium has to be activated to permit it to bind leukocytes, as a prelude to their exit from the blood vessels. 2. Transmigration across the endothelium (also called diapedesis ) 3. Migration in interstitial tissues toward a chemotactic stimulus
Table 3–4. Types of Acute Inflammation. Pyogenic bacteria, eg, staphylococci, streptococci, gram–negative bacilli, anaerobes. Exaggerated neutrophil response and liquefactive necrosis of parenchymal cells; pus formation. Marked neutrophil leukocytosis in blood. Suppurative (purulent) inflammation Toxigenic bacteria, eg, diphtheria bacillus ( Corynebacterium diphtheriae ) and Clostridium difficile. Necrotizing inflammation involving mucous membranes. The necrotic mucosa and inflammatory exudate form an adherent membrane on the mucosal surface. Membranous (pseudomembranous) inflammation Highly virulent organisms (bacterial, viral, fungal), eg, plague ( Yersinia pesti s), anthrax ( Bacillus anthracis ), herpes simplex encephalitis, mucormycosis. Marked tissue necrosis and hemorrhage. Necrotizing inflammation, hemorrhagic inflammation Many virulent bacterial infections. Excess fibrin formation. Fibrinous inflammation Infections, eg, common cold (rhinovirus); allergy (eg, hay fever). Marked secretion of mucus. Catarrhal inflammation (inflammation of mucous membranes) Burns; many bacterial infections. Marked fluid exudation. Serous inflammation (inflammation in body cavities) Certain hypersensitivity immune reactions Marked edema and numerous eosinophils; eosinophilia in blood. Allergic acute inflammation Viral and rickettsial infections (immune response contributes). Paucity of neutrophils in exudate; lymphocytes and plasma cells predominant; neutropenia, lymphocytosis in blood. Acute inflammation without neutrophils Bacterial infections; response to cell necrosis of any cause. Hyperemia; exudation with fibrin and neutrophils; neutrophil leukocytosis in blood. Classic type Common Causes Features Type
Suppurative or purulent inflammation is characterized by the production of large amounts of pus or purulent exudate consisting of neutrophils, necrotic cells, and edema fluid.
Serous inflammation is marked by the outpouring of a thin fluid that, depending on the size of injury, is derived from either the plasma or the secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities (called effusion ).
FIBRINOUS INFLAMMATION With more severe injuries and the resulting greater vascular permeability, larger molecules such as fibrinogen pass the vascular barrier, and fibrin is formed and deposited in the extracellular space
An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflammatory necrotic tissue
Chronic Inflammation Although difficult to define precisely, chronic inflammation is considered to be inflammation of prolonged duration (weeks or months) in which active inflammation , tissue destruction , and attempts at repair are proceeding simultaneously . Although it may follow acute inflammation, chronic inflammation frequently begins insidiously, as a low-grade, smoldering, often asymptomatic response. This latter type of chronic inflammation is the cause of tissue damage in some of the most common and disabling human diseases, such as rheumatoid arthritis, atherosclerosis, tuberculosis, and chronic lung diseases.
Chronic inflammation arises in the following settings: • Persistent infections • Prolonged exposure to potentially toxic agents, either exogenous or endogenous • Autoimmunity
In contrast to acute inflammation, which is manifested by vascular changes, edema, and predominantly neutrophilic infiltration, chronic inflammation is characterized by: • Infiltration with mononuclear cells , which include macrophages, lymphocytes, and plasma cells. • Tissue destruction , induced by the persistent offending agent or by the inflammatory cells. • Attempts at healing by connective tissue replacement of damaged tissue , accomplished by proliferation of small blood vessels ( angiogenesis ) and, in particular, fibrosis
Table 5–1. Differences between Acute and Chronic Inflammation. Frequently none; variable leukocyte changes, increased plasma immunoglobulin Neutrophil leukocytosis; lymphocytosis (in viral infections) Changes in peripheral blood Low–grade fever, weight loss, anemia Fever, often high Systemic manifestations Immune response, phagocytosis, repair Plasma factors: complement, immunoglobulins, properdin, etc; neutrophils, nonimmune phagocytosis Operative host responses + – Fibrosis (collagen deposition) + (ongoing) <ul><ul><li>– (Usually) </li></ul></ul><ul><ul><li>+ (Suppurative and necrotizing inflammation) </li></ul></ul>Tissue necrosis – + Cardinal clinical signs (redness, heat, swelling, pain) – + Fluid exudation and edema New vessel formation (granulation tissue) Active vasodilation, increased permeability Vascular changes Lymphocytes, plasma cells, macrophages, fibroblasts Neutrophils, macrophages Inflammatory cells Specific (where immune response is activated) Nonspecific Specificity Insidious Acute Onset Long (weeks to months) Short (days) Duration Chronic Acute
The products of activated macrophages serve to eliminate injurious agents such as microbes and to initiate the process of repair, and are responsible for much of the tissue injury in chronic inflammation. Tissue destruction is one of the hallmarks of chronic inflammation.
In short-lived inflammation, if the irritant is eliminated, macrophages eventually disappear (either dying off or making their way into the lymphatics and lymph nodes). In chronic inflammation, macrophage accumulation persists, and is mediated by different mechanisms
A granuloma is a focus of chronic inflammation consisting of a microscopic aggregation of macrophages that are transformed into epithelium-like cells surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells.