CHAPTER 2 Acute & Chronic Inflammation A key component of inflammation is the vascular response.

This is how inflammatory cells get to the site of injury. ACUTE INFLAMMATION - There are three components of the acute response. 1) vasodilation, 2) increased permeability of vessel walls, and 3) migration of inflammatory cells from the blood stream to the injury site. Acute inflammation commonly manifests 4 (or 5) clinical features: a) redness (rubor), b) swelling (tumor), c) heating (calor), and pain (dolor). Some also add loss of function (functio laesa) as a fifth.

Leukocyte Cellular Events MARGINATION AND ROLLING - Study Figure 2-4. Understand the relationship between selectins and integrins and how they cause rolling and adhesion. ADHESION AND TRANSMIGRATION - Once the inflammatory cell adheres, it must travel to the extravascular site of the injury. Intercellular adhesion molecules (ICAMs) allow for firm adhesion. The inflammatory cells, using a combination of platelet endothelial cell adhesion molecules (PECAMs) and the ability to "grasp" extracellular matrix material (like collagen), pull themselves outside the vessel (diapedesis). During the first day or two, PMNs predominate.

Vascular Changes: Changes in blood vesselsvasoconstriction - this is a brief reflex of arteries. Results in blanching.

CHEMOTAXIS AND ACTIVATION - A variety of substances act as chemical attractants for inflammatory cells. These cells also release substances which attract more cells, stimulates reproduction of their own kind, and makes them more mobile.

vasodilation - as the pipe diameter increases, the flow rate goes down but the amt of blood increases. The incr in blood flow (quantity) to the area (hyperemia) results in redness. (Fig 2-2)

PHAGOCYTOSIS AND DEGRANULATION - In order to clean up the injury site, phagocytes (histiocytes, macrophages, monocytes) engulf particles. In the case of bacteria, they must first be "opsoninized" to aid in their recognition by the phagocytes (IgG and C3b being most important). To degradate the microbes, the phagocyte produces free radials (oxygen species) (Fig. 2-7)

increased permeability of vessels - vessels are not a rigid tissue and they are lined with endothelial cells. As the diameter of the lumen increases, the endothelial cells become stretched and gaps open between them (and the cells contract as well widening the gap more). This allows the fluid component of blood to escape resulting in fluid accumulation in the soft tissues, edema, or swelling (tumor). As fluid escapes, the rate of blood flow slows even more resulting in stasis and compaction of blood cells. This causes increased viscosity of the blood in the "pipe." Cells migrate out of the vessels (transmigration or emigration)

Acute response is short lived, however, & cell population at injury site changes (see Figure 2-5)

contrast transudate and exudate. Text pg. 34

LEUKOCYTE-INDUCED TISSUE INJURY - Unfortunately, the killing is not completely selective. Like in any war, innocent lives (cells) are caught up in the process. In some disease (especially the autoimmune diseases) the damage caused by leukocytes can be as severe as, or worse, than the disease or injury itself.

PLASMA DERIVED: DEFECTS IN LEUKOCYTE FUNCTION some diseases are caused by poor leukocyte function. An example is Chdiak-Higashi syndrome. Chemical Mediators of Inflammation - Figure 2-14 a great summary. CELL DERIVED: VASOACTIVE AMINES - histamine and serotonin are important because they strengthen the inflammatory response and maintain it. LYSOSOMAL CONSTITUENTS- Granules in neutrophils and monocytes COMPLEMENT ACTIVATIONARACHIDONIC ACID PATHWAY - Arachidonic acid is a degradation product of cell membrane phospholipids. The 20 carbon, 4 double bond lipid is broken down in two pathways, cyclooxygenase and lipoxygenase pathways (Figure 2-15). These end products are major "players" in the inflammatory response and the range of signs and symptoms seen in inflammation. FIBRINOLYTIC SYSTEMPLASMA PROTEASES - from the clotting mechanism, the complement system, and kinins. Hageman factor - initiates the clotting cascade, the kinin cascade, and the complement cascade. (Study Figure 2-19 to grasp the interplay among these cascades).

A summary of the mediators in inflammation is found in Table 2-6. Outcomes of Acute Inflammation- One of four events (but there is overlap) 1. resolution - reverts back to the normal state. Damaged tissues regenerate. 2. scarring (fibrosis) - some tissue cannot regenerate or if damage is extensive, fibrosis fills in the defect resulting in a scar. This is also known as repair. 3. abscess formation - formation of pus, a form of liquefactive necrosis. 4. progression to chronic inflammation

PLATELET ACTIVATING FACTOR - also derived from cell membranes. A potent stimulus for vasocontriction and bronchoconstriction (a feature of asthma) and is an EXTREMELY potent vasodilator locally (much greater than histamine). CHRONIC INFLAMMATION - an inflammatory process which is prolonged (greater than a week or two??) which is characterized by 1) a mononuclear infiltrate (lymphocytes, plasma cells and macrophages), 2) tissue destruction, and 3) fibrosis. May last for years. Usually follows an acute response, but not always. The longer the persistence the greater the risk of significant fibrosis (scar). There are four basic processes involved with a chronic inflammatory process 1. persistence infections. May be from repeated re-infection or organisms of low virulence which stimulate a strong immune response such as TB. 2. prolonged exposure. Even relatively innocuous substances in high enough concentration and for long enough time can be harmful. Silica and asbestos are examples. Lipid intake and arterio-vascular disease another. 3. Autoimmune diseases. Here, the body recognizes self as foreign and since we cannot get away from self, these are ongoing chronic processes. Rheumatoid arthritis and SLE are examples. 4. viral infections

CYTOKINES - they are many, but Interleukin 1 (IL-1) and tumor necrosis factor (TNF) stimulate many responses (see Figure 2-16). These are polypeptides (hormone like substances) produced by lymphocytes and macrophages.

NITRIC OXIDE AND OXYGEN-DERIVED FREE RADICALS - NO has two major affects. It is a short-lived free radical that aids in microbial destruction along with OH0 and superoxide 020. (see Figure 2-17). NO also induces vasodilation (or more technically correct, smooth muscle relaxation).

Chronic Inflammatory Cells - basically mononuclear WBCs, or the cells derived from them. Macrophages - originated from bone marrow (moncytes), but once they reside in tissue they may have specialized names (Kupffer cell, microglia, sinus histiocytes, and alveolar macrophages). There are several substances macrophages produce when activated by lymphocytes. (Figure 2-21) proteases - both acid and neutral proteases, plasminogen activation. complement and coagulation cascades - C1 - C5, factors V and VIII oxygen species & NO eicosanoids ( arschadonic acid metabolites) cytokines - IL-1 and TN Others - T and B cells, plasma cells, and eosinophils (allergies and parasites).

Granulomatous Inflammation - characterized by activated macrophages (AKA epithelioid cells) Tuberculosis the quintessential granulomatous response. Foreign body reactions are also granulomatous. Table 2-7.

ROLE OF LYMPHATICS AND LYMPH NODES IN INFLAMMATION - drainage from sites of inflammation. Due to low pressure and rich lymphatic structure, overwhelming infections can return to the blood circulation via the thoracic duct or by escaping the lymphatics and "invading" the vasculature, creating a bacteremia.

MORPHOLOGIC PATTERNS IN ACUTE & CHRONIC INFLAMMATION - Morphology of inflamm depends on several factors: site/organ/tissue, virulence, and host resistance. serous inflammation - protein poor fluid (low specific gravity) referred to as effusion. A blister is an example as is "water on the knee." fibrinous inflammation - essentially blood plasma (with the fibrinogen) without many cells. Must be degraded by the fibrinolytic mechanism . The classic example is pericarditis resulting in restricted cardiac function. suppurative (purulent) inflammation - certain microbes are especially good at this such as Staph. aureus. Form abscess. Streps also can form abscesses and cellulitis. ulceration - loss of the surface covering.

SYSTEMIC EFFECTS OF INFLAMMATION - fever, acute phase reactants (TNF, IL-1, IL6). IL-6 induces fibrinogen production which increases sedimentation rate of RBCs. (ESR or erythrocyte sedimentation rate). Leukocytosis occurs. Bacterial infections tend to stimulate PMN reactions (neutrophilia), certain viruses such as mumps and measles stimulate leukocytosis (lymphocytic).