What are the cardinal signs of acute inflammation?
- Redness (erythema, rubor)
- Heat (warmth, calor)
- Pain (dolor)
- Swelling (edema)
- Loss of function (due to pain and swelling)
What is the pathogenic process of inflammation?
- 1: Changes in blood circulation
- 2: Changes in vessel wall permeability
- 3: Immune (WBC) response
- 4: Release of soluble mediators (cytokines)- interleukins, tumor necrosis factor (TNF), interferon γ, growth factors, others
What are the circulatory and vessel wall changes that occur during inflammation?
- Relaxation of smooth muscle cells on pre-capillary arterioles causing hyperemia redness, swelling, warmth.
- Increased pressure in capillaries/venules, causing edema.
- Vascular congestion (rouleaux formation)
- Margination of neutrophils and platelets (release of inflammatory mediators-interleukins).
What are the two classes of the mediators of inflammation?
- Plasma derived: circulate in inactive form, activated by specific/nonspecific activators
- Cell derived: preformed in granules/synthesized on demand
What are examples of biochemically heterogenous mediators of inflammation?
- Biogenic amines: histamine
- Peptides: bradykinin, complement
- Arachidonic acid derivatives: prostaglandins
What are the multifunctional effects of the mediators of inflammation on vessels and inflammatory cells?
- Altered vascular permeability
- Activation of inflammatory cells
- Chemotaxis (movement)
- Cytotoxicity (destructive to cells)
What plasma protein is similar to histamine but acts at a slower pace? What does it do?
- Increases vascular permeability, and is capable of inciting pain.
What cell derived mediator of inflammation is released by mast cells, basophils, and platelets?
What are the actions of histamine in the body?
- Increase vascular permeability.
- Promotes contraction of endothelial cells of venules.
- Leads to formation of gaps in lining of vessels (fluids and blood cells leaking into interstitial spaces).
- Results in swelling (edema)
- Cells now available in tissues to fight infection.
What are the pathways of the complement system?
- Classical PW
- Alternate PW
- Lectin PW
How are the complement system pathways activated?
- Classical: antigen-antibody complexes (immune response)
- Alternate: bacterial endotoxins, fungi, snake venom, and others
- Lectin: binding of plasma mannose-binding lectin to carbohydrates on bacteria
What are the critical functions of the complement system, and want are the biologically active intermed complexes and fragments involved with each?
- Opsonin (C3b+C3a): phagocytosis of bacterium
- Anaphylatoxins (C3b+C3a, C5b+C5a): histamine release, vasodilation, chemotactic fragments attract leukocytes
- Activated neutrophils (C567): leukotrienes amplify inflammatory response
- Membrane attack complex (C8+C9): cell lysis
Where is arachidonic acid derived from?
Phospholipids of cell membranes.
What are the two pathways in which arachidonic acid is metabolized?
- Lipoxygenase pathway
- Cyclo-oxygenase ("COX") pathway
Describe the lipoxygenase pathway (leukotrienes and lipoxins).
- Leukotrienes promote chemotaxis and vascular leak which cause anaphylactic shock and bronchospasm (some allergy meds reduce leukotrienes production).
- Lipoxins inhibit chemotaxis of leukocytes, therefore they are leukotriene mediated reactions.
Describe the cyclo-oxygenase ("COX") pathway.
- It forms...
- Prostaglandins: vasodilation, vascular leak, pain, fever
- Thromboxane: platelet aggreg, thrombosis, vasoconstriction (inhibited by COX inhibitors-anti inflammatory drugs; aspirin to inhibit platelet aggregation)
- Prostacyclin: counteracts thromboxane effects so they don't become extreme
Increased vascular permeability can result in transudate or exudate. What is the difference between these two?
- Transudate: slightly increased protein, no cells, fluid leak (edema)
- Exudate: markedly increased protein and inflammatory cells (emigration/diapedesis of cells across vascular wall in addition to fluid)
What is the predominant cell type in the exudate of acute inflammation?
What is the predominant cell type in the exudate of later stages of inflammation?
- Plasma cells
Described as the process by which leukocytes are attracted to bi-products of injury (against pressure gradient).
What attracts neutrophils to an area of injury?
- Products from bacteria
- Complement components (C5a)
- Arachidonic acid metabolites (ie. leukotrienes)
Described as dead and dying leukocytes, admixed with tissue debris and lytic enzymes.
What is the process of phagocytosis?
- PMNs travel to site of bacteria (chemotaxis)
- Opsonins facilitate binding of PMN to bacterium (C3b and C3a)
- PMN engulfs bacterium forming phagocytic vacuole
- Fusion of PMN granules (lytic enzymes within vacuole) destroys bacterium
Compare acute and chronic inflammation.
- Acute (minutes to days): immediate response, involves fluid (edema) and plasma proteins, exudate mainly neutrophils
- Chronic (days to years): includes vascular proliferation and scarring, mainly lymphocytes and macrophages
What are the first cells to appear in acute inflammation?
- PMNs (60-70% of all WBC in blood)
- Contain segmented nucleus, cytoplasm w/ granules, and is phagocytic.
What cell of inflammation usually appears 2-3 days after PMNs, and are prominent in allergic reactions and parasitic infection?
- Eosinophil (2-3% of all WBC in blood)
- Stained red (Greek "eos" means "rose colored")
What cell of inflammation is most prominent in allergic reactions mediated by IgE, and are precursors of mast cells?
- Basophils (<1% of all WBC in blood)
- Produce histamine (Type I hypersensitivity)
- Bean shaped single nucleus, larger than PMNs
What cell of inflammation appears 3-4 days after onset of infection or tissue destruction, and is capable of phagocytosis but not as efficient as PMNs?
- Macrophages (tissue mononuclear cells-histiocytes)
- Derived from blood monocytes
What cells of inflammation are fragments in cytoplasm released from megakaryocytes in marrow?
What are the substances the granules of platelets are filled with?
- Coagulation proteins
- Growth factors
When do platelets release their granules?
Upon contact with injured tissue (endothelial cells, thrombin formed in early clots, extracellular matrix).
What are the types of inflammation? What differentiates them?
- Serious: clear fluid w/out much protein
- Fibrinous: fibrin, debris from bacterial infection
- Purulent: pus
- Ulcerative: crater
- Pseudo-membranous: ulcerative with fibrino-purulent exudate
- Granulomatous: chronic inflammation
Which inflammation is the mildest form, has clear or slightly yellow fluid composed mostly of albumin and immunoglobulins, may be cause by virus, bacteria (mild), or physical agents?
Serious inflammation (2nd degree burns, Herpes, viral illnesses)
Which inflammation is a more severe form with an exudate rich in fibrin, thicker than serious and seen more in bacterial infections?
Fibrinous inflammation (bacterial pneumonia, "strep throat")
Which inflammation is from pus forming bacteria (strep/staph) that may accumulate on mucosa, skin, or in internal organs? How is this inflammation differentiated by location?
- Purulent inflammation
- Abscess: localized pus within an organ or tissue
- Empyema: localization of pus in a body cavity
Which inflammation is that which occurs on body surfaces or the mucosa of hollow organs (stomach/intestine), causing the loss of epithelial lining?
Which inflammation is of prolonged duration, marked by exudate containing lymphocytes, macrophages and plasma cells, and causes lass of parenchymal cells which results in scarring? What are some examples of destruction caused by this type of inflammation?
- Chronic inflammation
- Chronic PID leads to destruction of fallopian tubes
- Pulmonary fibrosis leads to impaired gas exchange causing dyspnea
Which inflammation is a form of ulcerative inflammation combined with fibrino-purulent exudate? What are examples of this form of inflammation?
- Pseudomembranous inflammation
- Corynebacterium diphtheriae (diphtheria)
- Clostridium difficile (pseudo-membranous colitis, abx associated, can cause GI perforation)
Which inflammation is a form of chronic inflammation typically NOT preceded by acute PMN-mediated inflammation, but instead has macrophages and fibroblasts wall off the area forming "giant" cells? What are some examples?
- Granulomatous inflammation
- TB, syphilis ("gumma"), fungi (histoplasma capsulatum), histoplasmosis, sarcoidosis (immunologically mediated).
What are the two processes of healing and repair?
- 1: replacement by connective tissue (scar)
- 2: regeneration of certain injured tissues (ie., skin)
What type of cells are continuously dividing and replacing themselves? What are some examples?
- Labile cells
- Hair, skin, GI tract, hematopoietic (blood cell forming)
- MOST affected by chemotherapy and radiation therapy.
What type of cells undergo few divisions but can be stimulated to divide more when needed? What are some examples?
- Stable cells
- Proximal renal tubules, liver (can regenerate to some extent).
What type of cells are incapable of division? Where are these cells found and how do they heal?
- "Permanent" cells
- Neurons, myocardium
- Healing accomplished by fibrous scarring.
- LEAST affected by chemotherapy.
What are the steps of wound healing?
- Hemostasis: vasoconstriction (initially then vasodilation), platelet activation, coagulation (fibrin, plts, RBCs form clot).
- Inflammation: removal of debris
- Proliferation: growing new cells (granulation tissue, epithelialization)
- Maturation (and scarring): collagen produced by fibroblasts increases causing scarring and wound contraction, eventually limited by collagenase
What are the most important cells that participate in healing? What is their role?
- PMNs: initial role in scavenging injury site
- Macrophages: produce cytokines, angioblasts, fibroblasts, myofibroblasts
How does the skin grow during epithelialization?
Up out of hair follicles and in from edges of wound (from basement membrane).
Why can't epithelialization occur with a full thickness skin loss?
No hair follicles, therefore no epithelialization from depth of wound.
Describe the process of epithelialization.
- Cells detach from basal layer and migrate in from wound edges.
- When cells meet, contact inhibition stimulates cell proliferation (mitogenic response mediated by epidermal growth factor).
- Basal cells differentiate into layers of new mature skin cells.
What is needed in order to cover a large full-thickness skin loss? How does it work?
- STSG (split-thickness skin graft)
- Skin epithelializes in openings of mesh.
Can a large surface area heal by way of epithelialization? What are examples of wounds that can heal by epithelialization?
- "skinned knee", partial thickness burn, small incision/laceration, originally large wound contracted enough for epithelialization to occur
What is the technical term for a scab, what does it consist of, and how does it facilitate epithelialization?
- Dried out tissue, serum, clot, proteins, inflammatory cells on wound surface.
- Hydrolytic enzymes under the eschar gradually separate it from wound surface (facilitates epithelialization).
What healing cells from macrophages are precursors of blood vessels, proliferate like sprouts from small blood vessels, and appear 2-3 days after injury?
What healing cells from macrophages produce most of the extracellular matrix? What provides attachment of these cells to a matrix in the wound milieu? What is the main protein of connective tissue associated with these cells?
- Collagen (comprises 25-35% of whole body protein, forms fibrils in interstitial spaces)
What healing cells from machrophages have hybrid properties of both smooth muscle and fibroblasts, contracting within a few days which reduces the size of the defect (wound), holding margins of tissue in close approximation?
What can happen to tubular structures (such as the bowel) if it has a wound that heals by contraction?
They can stricture and become narrow.
What is an undesirable effect of would contraction? How is this alleviated?
- Can cause contracture that limits motion.
- One way to overcome this is by Z-plasty.
What does epithelialization predominate over during wound healing by primary intention? How is this accomplished? What is the result?
- Edges of wound touch without tension.
- Minimal contracture or disfigurement results.
Explain wound healing by secondary intention.
- Edges of wound do not touch.
- Wound heals "by itself" (no sutures, staples, etc).
- More time is needed for healing than with primary intention healing.
- Shallow wounds heal by epithelialization.
- Deeper wounds heal by formation of granulation tissue, wound contraction, then epithelialization.
What kind of tissue is vascular connective tissue in a wound that consists of capillaries and fibroblasts? What is the old term for it? What does it look like?
- Granulation tissue
- "proud flesh"
- "Beefy" red appearance when "clean" (w/out invasive infection)
What are types of collagen and what are some examples?
- Type I (most common form): bone, skin, tendon, mature scars
- Type II: cartilage, vitreous humor, nucleus pulposus (part of spinal disc)
- Type III: embryonic tissues, blood vessels, uterus, GI tract, immature scars, and keloids
- Type IV: basement membranes
What are factors that favor wound healing?
- Size (smaller heals faster)
- Smooth edges & surfaces
- Little tension on edges
- Abundant vascular supply (depends on location)
- Good nutrition
What are factors that delay or impede repair?
- Retention of debris (foreign body)
- Impaired circulation
- Metabolic disorder (diabetes, renal)
- Corticosteroids (reversed by Vit A)
- Dietary deficiency of ascorbic acid (Vit C), protein, Zn, other nutrients
What are some complications of wound healing?
- Wound dehiscence: tension on edges cause separation, infection
- Incisional hernia: esp after abd wound infection with fascial dehiscence
- Hypertrophic scar: thicker than skin
- Keloid: scar grows tall and laterally wider than original wound (esp around shoulders, over sternum, and more common with dark skin)
How much tissue damage is a high velocity injury expected to impart as compared to a low velocity injury? Why?
- More tissue damage.
- Because more force is transmitted to the tissues.
What does a primary blast injury main affect?
Air filled organs: ears (perforated TM), lungs (pulmonary contusion, pneumothorax), bowel (perforation)
What is the cause of secondary blast injuries?
Injury due to projectiles.
What causes tertiary blast injuries?
- Being thrown by the blast (injury on impact).
- Crushed by falling objects.
What are quarternary blast injuries?