Inflammation part 1 Flashcards
Biology of tissue response to disease (inflammation)
acute inflammatory responses (patterns of response)
acute inflammation and mediator systems (histamine, prostaglandins, bradykinins, eosinophilic basic protein, nitric oxide)
vascular response to injury, including mediators principles of cell adherence and migration (eg, ECAMS, selectins, leukocytic diapedesis, and rolling)
microbicidial mechanisms and tissue injury (defensins)
clinical manifestations (pain, fever, leukocytosis, leukmoid reaction, chills)
reparative processes: wound healing, repair: trhombosis, granulation tissue, angiogenesis, fibrosis, scar/keloid formation regenerative process.
What is inflammation
A protective response involving host cells, blood vessels and proteins.
eliminate the initial cause of cell injury. Remove necrotic cells and tissue
initiate the process of repair
also a potentially harmful process: components of inflammation that are capable of destroying microbes can also injury bystander normal tissue.
What is inflammation 2
inflammation is a response of vascularized tissues to infections and damaged tissues that bring cells and molecules of host defense from the circulation to the sites where they are needed, in order to eliminate the offending agents.
components of the inflammatory process include white blood cells and plasma proteins
normally present in the blood
the inflammatory reaction’s goal is to bring these to the site of infection and/or tissue damage
inflammation is induced by chemical mediators produced by damaged host cells- cytokines and other mediators
inflammation is normally controlled and self limited
Excessive inflammatrion
can be pathogenic. In appropriate inflammatory response when there are no foreign substance to fight off leads to autoimmunity.
General features of inflammation
inflammation is a beneficial host response to foreign invaders and necrotic tissue, but it may also cause tissue damage. The main components of inflammation are a vascular reaction and a cellular response; both are activated by mediators that are dervied from plasma proteins and various cells.
The typical inflammatory reaction develops through a series of sequential steps:
the offending agent, which is located in extravascular tissues, is recognized by host cells and molecules
the leukocytes and proteins are activated and work together to destroy and eliminate the offending substance
the reaction is controlled and terminated.
the damage tissue is repaired.
What causes inflammation?
Microbial infections
hypersensitivity reaction
physical agents
chemicals
tissue necrosis
foreign bodies
immune reactions
acute inflammation
The initial and rapid response to infections and tissue damage. It typically develops within minutes or hours and is of short duration, lasting for several hours or a few days; its main characteristics are the exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, predominantly neutrophils (also called polymorphonuclear leukocytes). When acute inflammation achieves its desired goal of eliminating the offenders the reaction subsides, but if the response fails to clear the stimulus, the reaction can progress to a protracted phase that is called chronic inflammation. Chronic inflammation is of longer duration and is associated with more tissue destruction the presence of lymphocytes and macrophages, the proliferation of blood vessels, and the deposition of connective tissue. Acute inflammation is one of the reactions of the type of host defense known as innate immunity, and chronic inflammation is more prominent in the reactions of adaptive immunity.
Clinical features of acute inflammation
Rubor, calor, tumor, dolor, functiolaesa
Pathogenesis: vasodilation: increased blood flow. Brief intial vasoconstriction (pallor) is followed by vasodilation of arterioels and capillaries (redness and warmth)
Vascular leakage and edema: increased vascular permeability. loss of intravascular fluid and other blood components results in stasis of blood flow and the accumulation of fluid (exudate) in the interstitial tissues and/or body cavities. These account for swelling, pain, and loss of function
Leukocytes emigration to extravascular tissues: leukocytes accumulate at the site of injury in some types of inflammation. Neutrophils are the predominant cell in and are characteristic of acute inflammation. Margination and rolling, activation and adhesion, transmigration.
Vascular reaction of inflammation. Exudate. Transudate. edema. pus.
Changes in the blood flow and the permeability of vessels, both designed to maximize the movement of plasma proteins and leukocytes out of the circulation and into the site of infection or injury.
the escape of fluid, proteins and blood cells from the vascular system into the interstitial tissue or body cavities is known as exudation.
An exudate is an extravascular fluid that has a high protein concentration and contains cellular debris. Its presence implies that there is an increase in the permeability of small blood vessels triggered by some sort of tissue injury and an ongoing inflammatory reaction.
In contrast, a transudate is a fluid with low protein content (most of which is albumin), little or no cellular material, and low specific gravity. It is essentially an ultra filtrate of blood plasma that is produced as a result of osmotic or hydrostatic imbalances across the vessel wall without an increase in vascular permeability.
Edema denotes an 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.
Vascular stasis
The loss of fluid and increased vessel diameter lead to slow blood flow, concentration of red cells in small vessels, and increased viscosity of the blood. These changes result in engorgement of small vessels with slowly moving red cells, a condition termed stasis, which is seen as vascular congestion and localized redness of the involved tissue.
As stasis develops, blood leukocytes, principally neutrophils, accumulate along the vascular endothelium. At the same time endothelial cells are activated by mediators produced at sites of infection and tissue damage and express increased levels of adhesion molecules. Leukocytes then adhere to the endothelium, and soon afterward they migrate through the vascular wall into the interstitial tissue, in a sequence that is discussed later under cellular events.
Vascular leakage: endothelial injury and chemical response to injury.
retraction of endothelial cells resulting in increased interendothelial spaces in the most common mechanisms of vascular leakage. It is elicited by histamine, bradykinin, leukotrienes, and other chemical mediators. It is called the immediate transient response because it occurs rapidly after exposure to the mediator and is usually short lived (15 to 30 mins). In some forms of mild injury (e.g., after burns, irradiation, or ultraviolet radiation, and exposure to certain bacterial toxins.)
endothelial injury, resulting in endothelial cell necrosis and detachment. Indirect damage to the endothelium is encountered in severe injuries. e.g. injuries due to burns, or by the actions of microbes and microbial toxins that target endothelial cells. Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction
increased transport of fluid and proteins called transcytosis, through the endothelial cell. This process may involve intracellular channels that may be stimulated
Journey of leukocytes
from vessel lumen to the tissue is a multistep process that is mediated and controlled by adhesion molecules and cytokines called chemokines
- In the lumen: margination, rolling, and adhesion to endothelium. Vascular endothelium in its normal unactivated state does not bind circulating cells or impede their passage. In inflammation, the endothelium is activated and can bind leukocytes as a prelude to their exit from the blood vessels.
- migration across the endothelium and vessel walls
- migration in the tissue towards a chemotactic stimulus.
Rolling selectin
The initial rolling interactions are mediated by a family of proteins called selectins. There are three types of selectins: one expressed on leukocytes (L selectin), one on endothelium (E selectin), and one in platelets and on endothelium (P selectin). The Expression of selectins and their ligands is regulated by cotkines produced in response to infection and injury (TNF, IL-1, and chemokines or chemoattractant cytokines). Leukocytes express L selectin at the tips of their microvilli and also express ligands for E and P selectins, all of which bind to the complementary molecuels on the endothelial cells. These are low affinity interactions with a fast off-rate and they are easily disrupted by the flowing blood. As a result the bound leukocytes bind, detach, and bind again, and thus begin to roll along the endothelial surface
Adhesion integrins
these weak rolling interactions slow down the leukocytes and give them the opportunity to bind more firmly to the endothelium. Firm adhesion is medated by a family of heterdimeric leukocyte surface proteins call integrins. The combination of cytokine induced expression of integrin ligands on the endotheilium and increased integrin affinity on the leukocytes results in firm integrin mediated binding of the leukocytes to the endothelium at the site of inflammation. The leukocytes stop rolling, their cytoskeleton is reorganized and they spread out on the endothelial surface
transmigration
chemokines act on the adherent leukocytes and stimulate the cells to migrate through interendothelial spaces toward the chemical concentration grandient, that is, toward the site of injury or infection where the chemokines are being produced. Adhesion moelcules such as member of the immunoglobulin superfamily called CD31 or PECAM-1 (platelet endothelial cell adhesion molecules) present in the intercellular junctions between endothelial cells are involve din the migration of leukocytes.
