number 11 Done by Husam Abu-Awad Corrected by Muhammad Tarabieh Doctor Mousa Al-Abbadi
The possible outcomes of an acute inflammation are the following: 1- A complete resolution in which the tissue returns (almost) to its original state, this is the most common. 2- The acute inflammation persists for a long time and becomes chronic. 3- Fibrosis/scar formation occurs as the body tries to heal the inflamed tissue. If many inflammations occur in the same organ and each time healing is by fibrosis, after some time the organ no longer becomes functional and a transplant is needed (refer to the previous sheet). Chronic Inflammation The major cell infiltrates are macrophages, lymphocytes (polyclonal), sometimes (parasitic inflammation and allergic reactions) eosinophils and in other cases mast cells. Macrophages and lymphocytes have some form of coordination and feedback loop; mediators released by one regulate the activity of the other. (E.g. lymphocytes release lymphokines controlling the activity of the macrophages). The acute inflammation changes to a chronic inflammation when a virulent pathogen attacks and the acute inflammatory actions are not enough to eradicate it causing a prolonged inflammation lasting months or even years. [E.g. Mycobacterium TB and hepatitis C]. In most of the chronic inflammations there has been a preceding acute inflammation, but sometimes the chronic inflammation begins insidiously (no symptoms of acute inflammation) and it is only noticed when too much damage beyond repair has already occurred.
Causes of chronic inflammation: In the chronic inflammations, more tissue damage occurs compared to acute inflammations and also more healing attempts are done by the body and this is seen in angiogenesis (blood vessels formation) and fibrosis. In a chronic inflammation, you notice the presence of a cluster of small blue cells (see the mark in the first image), these are predominantly T-cells that are polyclonal and reactive. Also, the texture of the tissue begins to disappear. While in the second image (acute inflammation) where the tissue structure is still intact, there is some congestion and neutrophils only.
Cells and Mediators of Chronic Inflammations Macrophages They produce many mediators including TNF, IL-1, Chemokines, etc. They have a feed-back loop with the T-cells of the lymphocytes. Carry phagocytosis (so do the lymphocytes). Originate from circulating monocytes (half-life= 1 day). When the monocytes reach/ get recruited to the desired organ, they become a certain type of macrophage and their names change (see the mono-nuclear phagocytic system) and their half-lives increase a lot. The macrophages can be activated by two pathways: 1- M₁ classic pathway (stimulates inflammatory actions) 2- M₂ alternative pathway (inhibits inflammatory actions) Understand the following pathways: Classical macrophage activation: is induced by microbial products such as endotoxin, by T cell derived signals, importantly the cytokine IFN-γ, and by foreign substances including crystals and particulate matter. Classically activated macrophages produce lysosomal enzymes, NO, and ROS, all of which enhance their ability to kill ingested organisms, and secrete cytokines that stimulate inflammation. These macrophages are important in host defense against ingested microbes and in many chronic inflammatory reactions. Alternative macrophage activation: is induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytes and other cells, including mast cells and eosinophils. Alternatively activated macrophages are not actively microbicidal; instead, their principal role is in tissue repair. They secrete growth factors that promote angiogenesis, activate fibroblasts and stimulate collagen synthesis. It may be that in response to most injurious stimuli, macrophages are initially activated by the classical pathway,
designed to destroy the offending agents, and this is followed by alternative activation, which initiates tissue repair. However, such a precise sequence is not well documented in most inflammatory reactions. The macrophage before being activated (i.e. monocyte) has a large coffee bean like nucleus. When activated, the size of the cell increases, the cytoplasm increases and the nucleus becomes smaller (as more cytoplasmic organelles and proteins are made) nuclear cytoplasmic ratio is low. Note: Take it as a rule; the undifferentiated cell has a larger nucleus and a smaller cytoplasm than the differentiated one nuclear cytoplasmic ratio is high (seems like there are exceptions). Lymphocytes There are two major types, T and B lymphocytes. In the normal circulation there are more T-lymphocytes than B-lymphocytes. Also, T-lymphocytes are the main lymphocytes in chronic inflammatory reactions while a lot of B- lymphocytes indicates acute inflammation. Lymphocytes also require activation/recruitment usually directly by injurious agent. The T and B lymphocytes are polyclonal (we ll learn what that means in the future) which tells us that they are not originating from a tumour or neoplasia. B-lymphocytes exist in small amounts in chronic inflammation as the mature form (plasma cell), not the primitive B-lymphocyte. The most abundant lymphocyte is the CD4+ T-cells (also known as T-helper cells) (the CD4 refers to the surface receptors on the cell). These cells stimulate inflammatory actions. There are three main types of the CD4+ T-cells (left column): The right column shows the produced mediators by each T-helper cell type.
Eosinophils Called so because they show eosinophilia (pinkish cytoplasm) (remember Haematoxylin and Eosin stain). The nucleus is blue (very blue) and is bilobed (two-lobes). Cytoplasmic granules which contain enzymes that can cause tissue damage. Eosinophilic inflammations can happen anywhere in the body. -Function of Eosinophils: 1. These cells have receptors for the immunoglobulin E (IgE), which is produced by plasma cells, a major player in anaphylactic reactions. 2. response to parasitic infections. Mast Cells They are abundant in soft tissues (tendons, ligaments, fascia, skin, fibrous tissues, fat, and synovial membranes (which are connective tissue), and muscles, nerves and blood vessels (which are not connective tissue). These cells are active in both acute and chronic inflammations. Mast cells and basophils express a membrane protein given the symbol FCERI which binds with the FC portion of IgE. This results in degranulation of the mast cell and in the release of histamine and prostaglandins (seen in food allergies, drug allergies and venoms). In chronic inflammations mast cells release cytokines though they aren t the primary secretors. Primary secretors of cytokines are lymphocytes and macrophages. Neutrophils Neutrophils are seen in chronic inflammations but only in small quantities (not a major role). This happens, despite their short half-lives, when there are persistent microbes or continuous activation by the cytokines (in both cases new neutrophils come, the old ones quickly die - short half-life).
Chronic osteomyelitis. [This is a dangerous disease that begins as an acute inflammation with symptoms like redness near the leg, edema and fever, when you see these symptoms you MUST ask for a diagnostic test so that the disease can be cured, otherwise the inflammation becomes chronic and the effect is disastrous]. Lung damage by smoking attracts neutrophils to the region. Acute on top of chronic or acute exacerbation of chronic, these are terms used to describe a situation in which the patient has a chronic inflammation then an acute inflammatory attack occurs at the same site. (the acute inflammation attack brings neutrophils) Granulomatous Inflammation This is a special type of chronic inflammation (IT IS ALWAYS CHRONIC, NEVER ACUTE). A granuloma describes a situation seen under the microscope in which mainly activated macrophages (epithelioid histocytes) are pregnant, that is they have swollen cytoplasm and small nuclei, and are surrounded by T-helper cells (lymphocytes) and sometimes not always few plasma cells. Two types of granuloma: 1. The granuloma where necrosis is noted is called necrotising granuloma..itis (.. refer to the organ/tissue involved in the inflammation). also known as caseating granuloma mainly caused by infectious agents. 2. The granuloma where no necrosis is seen is called non-necrotising. A common cause of the necrotising granuloma is the Mycobacterium tuberculosis (anywhere in the body, not just the lungs). Fungi often cause the condition too. To test for the presence of TB a stain called acid fast bacilli stain is used, a positive result means TB is present. To test for the presence of fungi fungal stains have to be used. A common cause of the non-necrotising granuloma is the disease called sarcoidosis. You can only give a diagnosis of sarcoidosis when all other possible diseases are excluded (e.g. by seeing none of the microbes causing the
other diseases), this is a diagnosis by exclusion. This condition can be seen anywhere in the body, but is most common in the liver, lymph nodes and the lungs. To cure TB we use anti TB drugs, while to cure sarcoidosis we use steroids (remember steroids inhibits all immunity by inhibiting phospholipases refer to arachidonic acid metabolism). So, miss diagnosis of TB for sarcoidosis and treating TB with steroids is fatal. A third type of the granulomatous inflammation is that induced by a foreign body (e.g. tattoo, needle, etc.). Many WBCs gather around the foreign body and fuse together forming a giant cell that tries to destroy the foreign body. Note: There are some exceptions in the necrotising/non-necrotising classification, for example sarcoidosis can be seen with a necrotising granuloma.