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02 - January 15, 2013.docx

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02 – January 16, 2013 Beneficial and harmful effects of inflammation: Protect the host! – evolutionarily conserved Ex. Amoeba – engulf pathogens to protect itself; a more developed organism with vascular system, the entire vascular system employed in inflammation ADVERSE effects: tissue injury – may depend on location of inflammation; ex. Inflammation in eye may have long-term consequences for vision; Inflammation can be a significant pathogenic component to diseases Features of acute and chronic inflammation Predominant leukocyte recruited is neutrophil; can have some neutrophils for chronic inflammation, but generally mononuclear monocytes, so when go into tissues, differentiate into macrophages or dendritic cells or lymphocytes Acute is self-limiting so healing phase occurs after the acute response Different morphological features of these cells – histological sections Myeloid cells Neutorphils eosinophils – segmented nucleus – polymorphonuclear feature Moocytes – mononuclear – Lymphocytes also mononuclear nucleus – fewer vacuoles than monocytes Biopsy – acute inflammatory response – chronic inflammatory response – inflammatory response Vascular changes in inflammation – variety of different changes that occur in response to changes in vasculature Recruitment of leukocytes – occurs usually in interstitial and postcapillary venules First change is change in blood flow – on arterial sphincter – allow more blood to flow to site of inflammation – why is this blood flow important? More immune cells, and depends on efficiency of how blood can be extracted; deliver more cytokines; core temperature is 37 degrees, increase blood flow to extremities results in delivery of heat; Venus side of respose (above is arterial): increase in vascular permeability – known was edema This dilutes – provides plasma; the endotheial lining normally provides barrier to protens of high molecular weight, to be retained within vasculature; increase gaps between endothelial cells allows plasma proteins to leak out of blood into the extravascular space, provides factors in blood, like complements and cytokines, acess to the tissue where inflammation is occurring. Also, stretches the tissue and as result of the tissue, lead to pain. Swelling of tissue increases pressure in tissue, may lead to issues. In some organs, exudation of plasma from the from the blood into the extravascular tissue can lead to significant dysfunction of the organ; the brain would be sensitive to fluid accumulation in it, increasing cranial pressure, so less space between brain and skull; the space in skull is limited, if swelling in brain, ithe brain can only go down the spinal cord, compressing it, affecting the brain stem that regulates essential body functions, leading to death; another organ sensitive to edema is the lung; diffusion barrier is compromised, drown in own fluids; significant consequences – impact on variety of diseases – depend on where edema is located. Edema in arm – little long-term consequences on limbs; but in the brain and lung. Angiogenesis – formation of new blood vessels – generally occurs in chronic inflammation Inflammation in skin – redness can be due to two possibilities – increased blood flow to the skin, and microhemorrhages in the skin. Press on the skin, block blood supply; if skin blanches, then know increased blood flow; if hemorrhage, blood already in extra cellular tissues, Acute appendicitis – normal diameter is 1 cm; acute appendicitis diameter much bigger Leukocyte emigration Acute inflammation occurs in post-capillary venules – receptors around venules lacking in arterial side Recruitment of leukocytes, plasma leakages – on venule sides Microhemorrhages – leukocytes contribute to the damage – Leukocyte emigration Undergo migration – respond to chemotactic factors – mediators produced derived from plasma proteins – migration allows cells neutrophils – phagocytose the bacteria and degrade the bacteria within the phagolysosome – release of various leukocyte enzymes that lead to tissue injury If inflammation is severe locally, then the organism tries to wall off the inflammatory process and the inury is severe and destroy the tissue, and form the abscess (made up of pus, which is breakdown of leukocytes and tissue components and if caused by bacteria, will contain bacteria) – difficult to sterilize pus, because interrupt the blood supply – no blood supply to that area of necrosis – lower concentration of antibiotics than given reach the pus – high toxic environment, high compromised blood supply – dormant – most antibiotics target components of bacteria involved in bacterial proliferation Steps of leukocyte emigration – Transient adhesion – allow form bonds in front, break in the back – get rolling interaction – Stable, leads to arrest Change in cell cytoskeleton – flatten on endothelial cell surface – migration along surface called crawling – then diapedesis Sample the cells on endothelial surface – cells decide whether to continue migration or do enter Slows the cell – if cells do not make contact with endothelial, impossible to arrest Slowing down and sampling of endothelial cell surface of the main features of the rolling process Entire rocess is around ten minutes Endothelial cell activation Triggered by change in endothelial cells – normally in blood vessels, provide barrier to plasma protein leakage , generally non-adhesive cells – IL2, TNF – these cyotkines not affectin leukocytes but the endothelial cells, no effect on leukocytes alone; Endothelial cell activation These inflammatory cytokines work in endotheial cell surface – activate the surface through various receptors – Nuclear factor kappa B and MAP kinases – for epxresion of adhension molecules and chemokines by endothelial cells Allows leukocytes to undergo adhesion cascade Molecules expressed on endothelial cell surface – Inducible expression – Normally no adhesion because ekey adhesion molecules not present After cytokine stimulation – a number of adhesion molecules present and allow leukocytes to adhere Each of these adhesion molecules can be classified into different families – do not need to memorize – range of molecules present Selectins – Complexity of events that mediate these events – do not memorize Different molecules mediate different stages Biological activity of adhesion molecules Most molecules function as result of expression pattern If selectins not expression – do not get rolling Integrins – function is not dependent on expression – can change conformation from bent and non- functional conformation, through signallking steps due to chemokines, change conformation and becomes functional Mechanisms of leukocyte integrin activation during emigration – need to be presented on cell surface Regulation of leukocyte emigration – nature of inflammatory response determines type of cytokine produced locally, duration of cytokines produced at site of inflammation which influence endothelial cell biology, subtle When have acute inflammatory response – neutrophils rolling along surface – activated because recognize g coupled receptors – allows neutrophils to arrest and undergo later stage of recr
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