Inflammation

Inflammation

1. Response

   • Non specific response, all the steps of inflammation will occur. If it is triggered it cannot be stopped until body figured out what it needs.
   • Begins with Mast Cells (cellular bags of granules located in loose connective tissue)
     • Cause Allergies
     • Respond to pathogens
     • Cross legs for too long, mast cells trigger cell death- causing pin and needles

2. Noxious Stimuli

   • Mast Cell Degranulates
     • Release of histamines and other chemicals are the immediate response
       • Causes vascontriction, limiting breathing Does not last very long. 
     • Mast Cell Synthesis
       • Leukotrienes
         • Keep inflammatory response going until stimuli is removed.  Signal immune system (WBCs), have similar effects to histamine
       • Prostaglandins
         • Increase vascular permeability, neutrophil chemotaxis, and pain Suppresses release of histamine..
       • Cytokines (TNF-alpha and IL-13)
         • Increased vascular permeability, chemotaxis, B-cell proliferation and antibody production.    Make blood more viscous       
       • Growth Factors
         • Platelet activating factor, platelet derived growth factor, vascular endothelial growth factor.  These will allow for healing of tissue, if there was no tissue injury then they will not be released. 
       • Vascular Response
         • Histamine release triggers a temporary rapid constriction of large vessel walls then vasodilation and increased capillary permeability.- allows flow of plasma into surrounding tissue Blood becomes more viscous and flows more slowly through the area. 
       • Cellular Response
         • Release of histamine also triggers the release of chemotaxic factors. Leukocytes (beginning with neutrophils) begin to arrive at the site and begin to emigrate into the tissue.  Process of margination- neutrophils and blood borne monocytes stick to the inner lining of the capillaries in the affected area.  Selectins protruding from vessel, catch integrins located on the plasma membrane of the leukocye. Cytokines causes certain leukocytes to anchor as well. 
         • Diapedesis alters leukocytes and allows it to move out of the vasculature and into the tissue.
         • Chemotaxins are released, attracting phagocytic cells to site of injury
         • Phagocytosis is the process by which a cell ingests and disposes of foreign material
           • Phagocytes are dendritic cells, no relation to nervous system
             • Neutrophils
               • Predominate in early inflammatory responses. Ingests bacteria, dead cells, and cellular debris. Cells are short lived and become a component of the purulent exudate.
             • Monocytes
               • Monocytes are produced in bone marrow, enter circulation, and migrate to the inflammatory site, where they develop into macrophages
             • Macrophages
               • Active 3-7 days after neutrophils. Phagocytic, secrete cytokines/growth factors that stimulate inflammation Initiation of healing
             • Eosinophils
               • Primary defense against parasites Regulate vascular mediators from mast cells Mild phagocytosis
             • Basophils
               • Role uncertain
             • Natural Killer Cells
               • Recognize and eliminate cells infected with viruses and some function of eliminating cancer cells. 
       • Plasma Protein Systems
         • Occuring at the same time as cellular and vascular response Systems will be activated based on mediators that are present
         • Complement System
           • Perpetuates Inflammation Causes bacterial cell lysis
           • Classical Pathway
             • Activated by antibody/antigen complexes
           • Lectin Pathway
             • Activated by bacterial carbs
           • Alternative Pathway
             • Activated by gram-negative bacterial and fungal  wall polysaccarides
         • Clotting System
           • Forms fibrous meshwork to stop bleeding, provides framework for repair and healing. Activated by substances released during tissue destruction/ infection and by bacterial products
           • Extrinsic Pathway
             • Activated when tissue thromboplastin from injured epithelial cells interacts with Factor CII
           • Intrinsic Pathway
             • Activated when Factor XII from plasma comes in ocntact with injured vessel walls.
         • Kinin System
           • Activated by collagen and other substances. Final product is bradykinin- cause dilationof blood vessels and vascular permeability as well as pain signals

3. Products of Inflammation

   • Cytokines
     • Polypeptides produced in response to microbes and other antigens that mediate and regulate immune responses.
     • Interleukins
       • Pro- inflammatory versus anti-inflammatory Endogenous pyrogens
     • Interferons
       • Protect against viral infections, modify inflammation.  Interferons binds to uninfected cell and induces synthesis of antiviral protein. Antiviral protein blocks viral nucleic acid synthesis
     • Tumor Necrosis Factor - Alpha (TNF-a)
       • Secreted by macrophages in response to pathogens.  -Induces fever by acting as endogenous pyrogen (protein that induces fever) Increases synthesis of inflammatory serum proteins Causes muscle wasting (Cachexia) and intravascular thrombosis. 
   • Platelet Activating Factor
     • Circulating platelets are activated by products of th innate and adaptive immune systems after an injury occurs Activation results in interaction with the clotting system to stop bleeding
   • Nitric Oxide
     • Causes local arterial vasodilation Keeps blood vessels smooth so that blood can flow more easily

4. Signs of Inflammation

   • Redness, Swelling, Pain, Heat
   • Fever
     • Response to pyrogens that stimulate prostaglandin synthesis
   • Leukocytosis
     • Accelerated release of leukocytes from BM "left shift" occurs when immature neutrophils (bands) are released
   • Acute Phase Protein Synthesis
     • Synthesized int he liver in increased numbers in response to inflammatory cytokines C-Reactive Protein ESR- estimate sedimentation rate

5. Chronic Inflammation

   • Inflammaton Lasting longer than 2 weeks Macrophages prodominate- eliminate microbes, but are responsible for much of the tissue destruction seen in chronic inflammation

6. Disorders

   • Gout
     • Disorder of uric acid metabolism NOT a disease of the joints Genetic overproducers: some people coverts glycine directly to uric acid Lesch-Nyhan Syndrome- gout and mental retardation in children Von Gierke's Type 1 Glycogen storage disease
   • Reumatoid Arthritis
     • Autoummune disorder, inflammation of the synovial lining of the joints.

7. Drugs

   • Steroidal Anti Inflammatory
     • Block the action of phosphlipase Cortisone Hydrocordisone
     • Corticosteroids
       • Hormones produced by the adrenal cortex
       • Glucocorticoids
         • Have anti-inflammatory effects due to their inhibition of phospholipase Raise the concentration of liver glycogen and increase blood glucose levels Affect carbs, proten, and fat metabolism Regulated by negative feedback
         • Short Acting <12 hours
           • Cortisone and hydrocortisone
         • Intermediate Acting (12-36 hours)
           • Prednisone, prednisolone..
         • Long Acting (>36 hours)
           • Dexamethason, betamethasone, fluocinolone
       • Mineralcorticoids
   • Non Steroidal Anti Inflammatory
     • Blocks the action of cycloocygenase Aspirin Ibuprofen Naproxen Sodium Work by inhibiting cyclooxygenase ( 2 forms: COX-1 (involved in stomach) and COX-2 (involved in inflammation) Referred to as prostaglandin inhibitors Fewer side effects than glucocorticoids
     • Salicylates
       • Potent inhibitors of prostaglandin synthesis (Aspirin) Side effects are GI Problems
     • Propionic Acid Derivatives
       • Block cyclooxygenase and lipoxygenase (Ibuprophen, ketoprofen, carprofen) (-fen drugs) Side effects ( GI problems and possible liver toxicities)
     • COX-2 Inhibitors
       • Inhibit cyclooxygenase -2 without interferring with the protective cyclooxygenase-1) (Deracoxib, meloxicam) Side effects: Anorexia, vomitign, lethargy