Inflammation: local defensive response of living tissues to injurious agents Inflammation is a defensive process thata living body initiates against local tissue damage. It takes the form of a complex reaction of blood vessels, certain plasma components and blood cells, and cellular and structural components of connective tissue. + Terms ending in the suffix “-itis” denote inflammation. (e.g. Dermatitis: Inflammation of the skin, Osteomyelitis: Inflammation of the bones) In simple terms, inflammation can be defined as a beneficial, nonspecific response of tissues to injury that generally leads to restoration of normal structure and function. Historical aspects The word inflammation came from Latin word inflammarewhich means to set on fire. Celsus Roman Writer in 1” century AD listed the four signs of inflammation. He described a typical inflammatory response as “redness and swelling with heat and pain”. Signs of Inflammation The Cardinal Signs of Acute Inflammation are RUBOR- redness CALOR. increase heat TUMOR: swelling DOLAR- pain in inflamed area FUNCTIO LAESA- loss of function due to necrosis Types of inflammation There are two broad categories of inflammation 1. Acute inflammationis rapid in onset (seconds or minutes) and is of relatively short duration, lasting for minutes, several hours, or a few days. The tissue damage in case of acute inflammation is mild and it is often selflimited. Its main cheracteristics are the exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, mainly neutrophils / polymorph nuclear inflammatory cells. 2. Chronic inflammation is of longer duration and is essociated histologically with the presence of mononuclear inflammatory cells (lymphocytes and macrophages), the proliferation of blood vessels, fibrosis, and tissue necrosis. The tissue injury in case of chronic inflammation is very severe and progressive in nature. ees, am nomic OnE) opi. in minyhe siondays [GE eutrophie Lymphocytes monoetes Imazrophoaes Mid, set severe Tite prose ES ceminee Less rommentStimuli for acute inflammation / Etiology of Inflammation + Physical agents: « extreme temperatures, electric shock, radiation, mechanical injures, ete. + Chemical agents: « Products of metabolism, acids, alkalis, drugs + Biological agents: « Microorganisms (bacteria, viruses, fungi), parasites (helmints, insects), immune cells and complexes Steps of Inflammatory response: (The 5 "R’s of Inflammatory Response) Recognition of the injurious agent Recruitment of inflammatory cells Removal of the injurious agents Regulation (control of inflammatory response) Resolution/Repair 1. Recognition of the stimuli The process of acute inflammation is initiated by resident immune cells already present in the involved tissue (local immune cells), mainly resident macrophages, dendritic cells, and mast cells. These cells possess surface receptors known as pattern recognition receptors (PRRs), which recognize (i.e., bind) two subclasses of molecules: pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pattems (DAMPs) (Note: PAMPs are compounds that are associated with various pathogens, but which are distinguishable from host molecules. DAMPs are compounds that are associated with host-related injury and cell damage) At the onset of an infection, burn, or other injuries, these cells undergo activation (one of the PRRs recognize a PAMP or DAMP) and release inflammatory mediators responsible for the clinical signs of inflammation. For example: Prostaglandins and other substances (promote blood flow to the site of injury) released by leukocytes and damaged tissue cells. Histamine (mostly involve in vascular changes): released by mast cells in connective tissues. Effects of chemical mediators: acute inflammation can be seen with the following changes due to release of histamine and other chemical mediators ‘A. Vascular Changes As the tissue exposed to stimuli the first thing happen is vascular change, which include: i. Changes in the vascular flow - due to vasodilation: When tissue is first injured, the first event is vasodilation/ vasodilatation, which is brought about by the histamine. This results in increased blood flow to bring cells and proteins to the site of injury (causing redness and heat) ii, Increased in vascular permeability: Next. the walls of the blood vessels (which normally allow only water and salts to pass through easily) become more permeable. Protein-rich fluid - called exudate, is now can pass throughthe blood vessels and exit into the tissues. * Substances in the exudate include clotting factors, which help prevent the spread of infectious agents throughout the body. Other proteins include antibodies that help destroy invading microorganisms. iii, Vascular stasis it is the event of slowing of the blood in the bloodstream with vasodilation and fluid exudation to allow chemical mediators and inflammatory cells to accumulate and respond to the stimulus Results of Vascular Changes: Enhanced blood flow and vessel permeability have several effects: including © Delivery of clotting factors to the injured area: clotting marks the beginning of the repair process and helps block the spread of microbes. * Second, increased blood flow and vessel permeability increase the migration of phagocytic cells from the blood into the injured tissues (diapedesis), B. Cellular changes As fluid and other substances leak out of the blood vessels, blood flow becomes slower (vascular stasis) and white blood cells begin to flow nearer the vessel wall The white blood cells then adhere to the blood vessel wall - the first step in their emigration into the extravascular space of the tissue — diapedesis. Note: The most important feature of inflammation is the accumulation of white blood cells at the site of injury. Most of these cells are phagocytes. The main phagocytes involved in acute inflammation are the neutrophils, a type of white blood cell that contains granules of cell-destroying enzymes and proteins. When tissue damage is slight, an adequate supply of these cells can be obtained from those already circulating in the blood. But, when damages extensive, stores of neutrophils —some in immature form—are released from the bone marrow. 2. Recruitment of phagocytic cells: To perform their tasks, not only must neutrophils exit through the blood vessel wall but they must actively move from the blood vessel toward the area of tissue damage. This movement is made possible by chemical substances called chemotactic factors or chemokines, secreted by many cells, including blood vessel endothelial cells and monocytes. The one-way migration of phagocytic cells along the concentration gradient is called chemotaxis Large numbers of neutrophils reach the site of injury first, sometimes within an hour after injury or infection. After the neutrophils, often 24 to 28 hours after inflammation begins, there comes another group of white blood cells, the monocytes, which eventually mature into cell-eating macrophages. Macrophages usually become more prevalent at the site of injury only after days or weeks and area cellular halimark of chronic inflammationNote: /n addition to cell-derived mediators, several acellular biochemical cascade systems consisting of preformed plasma proteins act in parallel to initiate and propagate the inflammatory response. These include the complement system activated by bacteria and the coagulation system activated by necrosis, e.g. a burn or a trauma 3. Removal of the stimuli: removed by phagocytosis The stimuli or injurious agent which may be physical, chemical or biological agent, is removed mainly by phagocytosis coupled with other defensive mechanism including degranulation, complement system and antibodies production. 4, Regulation The process of inflammation is properly regulated On one hand, inflammation is essential to resolve tissue injury and maintain homeostasis. On the other, inflammation is ¢ key participant in the great majority of human diseases. Accordingly, to achieve complete resolution of inflammation, it is necessary to both turn off inflammatory mediator production and inflammatory cell accumulation and to remove inflammatory cells and debris without initiating an autoimmune response. Much of this process involves key activities of anti-inflammatory cytokines released by the mononuclear phagocytic cells, including resident and recruited macrophages. To regulate and resolve inflammatory response, antiinflammatory cytokines e.g. 1L-10 (interleukine-10) inhibits the production of histamine and other pro- inflammatory cytokines. 5. Repair and healing As the inflammation subsides, proliferation becomes a major theme with the focus on covering the wound surface (i.e., re-epithelialization), restoring the vascular network and forming granulation tissue. Re-epithelialization requires migration and proliferation of keratinocytes. In a few hours to 1 day after injury, the existing wound-edge keratinocytes start to migrate. To generate more cells to cover the wound, keratinocytes at the basal layer of the wound edge and epithelia stem cells from nearby hair follicles or sweat glands start proliferating approximately 2-3 days after injury. Restoring the network of blood vessels is important, since nutrients and oxygen are needed during wound repair. The process of new blood vessel formation, also known as ‘angiogenesis, is initiated by growth factors, e.g,, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and the serine protease thrombin in the wounds, which activate the endothelial cells of existing vessels Note: During the healing process, damaged cells capable of proliferation regenerate. Different types of cells vary in their ability to regenerate. Some cells, such as epithelial cells, regenerate easily, whereas others, such as liver cells, donot normallyproliferate but can be stimulated to do so after damage has occurred. Still other types of cells are incapable of regeneration. For regeneration to be successful, it is also necessary that the structure of the tissue be simple enough to reconstruct. For example, uncomplicated structures such as the flat surface of the skin are easy to rebuild, but the complex architecture of a gland is not. In some cases, the failure to replicate the original framework of an organ can lead to disease. This is the case in cirrhosis of the liver, in which regeneration of damaged tissue results in the construction of abnormal structures that can lead to hemorrhaging and death. Repair, which occurs when tissue damage is substantial or the normal tissue architecture cannot be regenerated successfully, results in the formation of a fibrous scar. Through the repair process, endothelial cells give rise to new blood vessels, and cells called fibroblasts grow to form a loose framework of connective tissue. This delicate vascularized connective tissue is called granulation tissue. It derives its name from the small red granular areas that are seen in healing tissue (e.g,, the skin beneath a scab). As repair progresses, new blood vessels establish blood circulation in the healing area, and fibroblasts produce collagen that imparts mechenical strength to the growing tissue. Eventually a scar consisting almost completely of densely packed collagen is formed. The volume of scar tissue is usually less than that of the tissue it replaces, which can cause an organ to contract and become distorted. For example, scarring of the intestines can cause the tubular structure to become obstructed through narrowing. The most dramatic cases of scarring occur in response to severe burns or trauma. The series of events in the process of inflammation are: (The basis of the five cardinal signs) * — Vasodilation: Vasodilation and its resulting increased blood flow causes the redness (rubor) and increased heat (calor) * Increased vascular permeability results in an exudation (leakage) of plasma proteins and fluid into the tissue (edema), which manifests itself as swelling (tumor) * Certain chemical mediators such as bradykinin stimulate sensory nerve endings giving pain (hyperalgesia, dolor). Nerves also stimulated by stretching from oedema + Pain and swelling result in loss of function. Suppuration The process of pus formation, called suppuraticn, occurs when the agent that provoked the inflammation is difficult to eliminate. Pus is a viscous liquid that consists mostly of dead and dying neutrophils and bacteria, cellular debris, and fluid leaked from blood vessels. The most common cause of suppuration is infection with the pyogenic (pus-producing) bacteria, such as Staphylococcus and Streptococcus. Once pus begins to collect in a tissue, it becomes surrounded by a membrane, giving rise to a structure called an abscess. Because an abscess is virtually inaccessible to antibodies and antibiotics, it is very difficult to treat. Sometimes a surgical incision isnecessary to drain and eliminate it. Some abscesses, such as boils, can burst of their own accord. The abscess cavity then collapses, and the tissue is replaced through the process of repair.Chronic inflammation If the agent causing an inflammation cannot be eliminated, or if there is some interference with the healing process, an acute inflammatory response may progress to the chronic stage. Repeated episodes of acute inflammation also can give rise to chronic inflammation. The physical extent, duration, and effects of chronic inflammation vary with the cause of the injury and the body's ability to ameliorate the damage. In some cases, chronic inflammation is not @ sequel to acute inflammation but an independent response. Some of the most common and disabling human diseases, such as tuberculosis rheumatoid arthritis, and chronic lung disease, are characterized by this type of inflammation. Chronic inflammation can be brought about by infectious organisms that are able to resist host defenses and persist in tissues for an extended period. These organisms include Mycobacterium tuberculosis (the causative agent of tuberculosis), fungi, protozoa, and metazoal parasites. Other inflammatory agents are materials foreign to the body that cannot be removed by phagocytosis or enzymatic breakdown. These include substances that can be inhaled, such as silica dust, and materials that can gain entry to wounds, such as metal or wood splinters. In autoimmune reactions the stimulus to chronic inflammation is a normal component of the body to which the immune system has become sensitized. Autoimmune reactions give rise to chronic inflammatory diseases such as rheumatoid arthritis. The hallmark of chronic inflammation is the infiltration of the tissue site by macrophages, lymphocytes, and plasma cells (mature antibody-producing 8 lymphocytes). These cells are recruited from the circulation by the steady release of chemotactic factors. Macrophages are the principal cells involved in chronic inflammation and produce many effects that contribute to the progression of tissue damage and to consequent functional impairment. Granulomatous inflammation is a distinct type of chronic inflammation. It is marked by the formation of granulomas, which are small collections of modified macrophages called epithelioid cells and are usually surrounded by lymphocytes Granulomas often contain giant, or Langhans, cells that form from the coalescence of epithelioid cells. A classic example of granulomatous inflammation is tuberculosis, and the granulomas formed are called tubercles. Granulomas also typically arise from fungal infections, and they are present in schistosomiasis, syphilis, and rheumatoid arthritis.