Week 1: Inflammatory Response

• Inflammatory Response


  A biochemical response that occurs in vascularized tissue in response to cell injury
• Causes of inflammation


  • Exogenous (trauma)
  • Endogenous (tissue ischemia)
  • Infection
  • Ischemia (deprivation of oxygen to tissue)
  • Mechanical injury
  • Nutrient deprivation
  • Chemical agents, ionizing radiation, temperature extremes
• Inflammatory Response


  • Nonspecific - happens the same way regardless of the stimulus
  • Part of the innate immune system
  • Acts at both local and systemic levels
  • May be acute or chronic
  • Consists of a vascular response and cellular response
• Vascular Response


  1. Vasoconstriction (brief) stops bleeding

  2. Vasodilation of arterioles

  3. Increased blood flow to site (redness, warmth)

  4. Chemical substances* released resulting in increased vascular permeability

  5. Edema, increased viscosity of blood, clotting in small capillaries
• Chemical substances*


  Histamine, kinins, prostaglandins, leukotrienes, and complement
• Pain & impaired function


  Follow as a result of tissue swelling
• Vascular Response


  1. Platelets aggregate to form initial platelet plug & stop bleeding

  2. Clotting cascade activated

  3. Begins to form fibrin & fibrinous network traps platelets & other cells (WBCs & RBCs)

  4. Forms stable clot covers wound while it heals
• Vascular response


  • Observable symptoms: redness, heat, swelling, pain, loss of function
• Vasoactive Chemicals in Inflammation


  Histamine, Prostaglandins, and Leukotrienes
• Histamine


  • Released by mast cells: cause epithelia cells to contract leading to increased vascular permeability
  • Also cause bronchial constriction and mucus production
• Prostaglandins


  • Phospholipid compound formed arachidonic acid
  • Arise from cyclooxygenase (COX) pathway can be inhibited by drugs that block enzymes in this pathway
  • Vasodilation and increased permeability
  • Prostaglandin D2 is chemotactic factor and stimulate neutrophil emigration to site
  • Enhanced sensitivity of pain receptor causing pain
• Leukotrienes


  • Phospholipid compound formed from arachidonic acid
  • Five types from lipoxygenase pathway
  • Potent chemotaxtic agent, smooth muscle contractions, bronchospasms and increased vascular permeability
  • Blocked by leukotriene receptor blocker agents Montelukast - leukotriene receptor antagonists
• Cellular Response


  1. Neutrophils guided to injured tissues by adhesion molecules and chemotaxis

  2. Are most abundant and first on the scene

  3. Begin phagocytosis and degrade dead tissue

  4. Short-lived, die while fighting infection

  5. Monocytes (called macrophages in tissues) are slower

  6. Live longer

  7. Phagocytosis, secrete cytokines, antigen presentation
• Other cells involved in cellular response


  • Basophils (in vascular system), Mast cells in CT
  • Eosinophils (hydrolases and peroxidases)
  • NK cells (good for viral infections and opsonization of bacteria)
• Phagocytosis


  • Neutrophils and Macrophages specialize in collagen and extracellular degradation
  • Pus: dead neutrophils, bacteria, cellular debris
  • Oxidizing agents result from phagocyte oxidase enzyme system in lysosomes
  • α1-Antiproteases – made in liver – a system of inactivators that inhibit destructive proteases released from neutrophils
• Types of inflammatory exudate


  • Serous – watery, low protein
  • Serosanguineous – pink-tinged, blood in fluid
  • Fibrinous – sticky and thick
  • Purulent (pus) – neutrophils, protein, tissue debris
  • Hemorrhagic – red blood cells, severe inflammation
• Systemic Response of Acute Inflammation


  1. Fever: Endogenous pyrogens (IL-1, IL-6, TNFα) produced by neutrophils and macrophages

  2. Act on the hypothalamus

  3. TNF also leads to lethargy and decreased appetite

  4. Enhanced muscle catabolism, increase pool of amino acids

  5. Increased Plasma Proteins: Acute Phase Reactants

  6. Leukocytosis: Increased leukocytes

  7. "shift to the left" – increase in immature neutrophils
• "Shift to the left"


  • A reflection of immature neutrophils called bands from the bone marrow
  • An increased ratio of bands to mature neutrophils
  • Commonly seen in acute bacterial infections
• Acute Inflammation


  • Lasting less than 2 weeks (usually 8-10 days)
  • Infiltration mainly with neutrophils
  • Proliferation of exudates
• Chronic Inflammation


  • Lasting more than 2 weeks, recurrent or progressive acute inflammatory process
  • Dense infiltration of macrophages and lymphocytes
  • Granulomas may form if neutrophils and macrophages cannot destroy microorganisms
• Acute Phase Reactants


  • Maximal levels within 10-40 hours of infection
  • IL-1, IL-6, TNF-α stimulate liver to release acute phase proteins (complement, clotting factors, protease inhibitors- α1 antitrypsin)
  • Increased fibrinogen, clotting components, complement components, C-reactive protein (CRP)
  • Erythrocyte sedimentation rate (ESR) increased dt coating of RBCs by acute phase proteins causing aggregation
  • CRP and ESR are nonspecific indicators of inflammation
• Chemical Mediators of Inflammation


  • Complement
  • Kinins
  • Clotting factors
  • Cytokines and Chemokines
• Complement Cascade


  1. ~ 20 plasma proteins synthesized in the liver and by macrophages that interact to enhance inflammation, facilitate phagocytosis by opsonization, chemotaxis and lysis of target cells

  2. Proteins circulate as inactive form. When first proenzyme in system is activated, triggers the activation of the cascade.
• Hageman Factor


  • Inflammation
  • Intrinsic Pathway of Clotting Cascade
• Kinin System


  • Activated form of Hageman factor (XII) stimulates plasma kinin cascade which result in bradykinin formation
  • Causes smooth muscle contraction
  • Increases leukocyte chemotaxis
• Clotting Cascade


  1. Forms a clot -> stops bleeding

  2. Walls off inflammation prevents spread

  3. Framework for healing & repair

  4. Hageman Factor (XII) made in the liver

  5. Prothrombin

  6. Intrinsic pathway is clinically measured as the partial thromboplastin time (PTT) while the extrinsic pathway is measured by prothrombin time (PT)
• Cytokines


  • Polypeptide molecules that form a complex intercellular communication network released from immune cells
  • Functions include: Inflammatory mediators, Chemotasis, Intercellular communication, Growth factors and inhibitors, Pyrogen: fever-regulating center in hypothalamus to raise core body temp
  • Macrophages and lymphocytes are important sources of immune cytokines
• Proinflammatory cytokines


  • Produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions
  • IL-1β, IL-6, and TNF-α are the typical proinflammatory cytokines
• Histamine


  • Stored in Mast Cells
  • Vasodilation, increased capillary permeability
  • Congestion in area (pain and swelling)
  • Two types of histamine receptors:
  • H1: smooth muscle of vascular system, bronchial tree, and digestive tract
  • Itching, pain, edema, vasodilation, bronchoconstriction and inflammation and allergy
  • H2: primarily in stomach
  • Secretion of large amounts of hydrochloric acid
• Specific Antagonists for H1 and H2


  • H1-receptor antagonists (antihistamines):
  • Dyphenhydramine (Benadryl and others)
  • Promethazine (Phenergan and others)
  • Cetirizine (Zyrtec)
  • Fexofenadine (Allegra)
  • Loratadine (Claritin)
  • H2- receptor antagonists:
  • Cimetidine (Tagmet)
  • Famotidine (Pepcid, Mylanta AP)
  • Ranitidine (Zantac)
• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)


  • Analgesic, Antipyretic, and anti-inflammatory properties
  • Aspirin
  • Ibuprofen (Motrin, Advil)
  • Ibuprofen-like drugs (Naproxen- Aleve)
  • Cyclooxygenase (COX) inhibitors
  • COX 1- in all tissues, protective effect smooth muscles, vascular system, gastric secretion reduction
  • COX-2 – present only after tissue injury, promotes inflammation
  • Acetaminophen (Tylenol) has analgesic and antipyretic effects but not anti-inflammatory and is NOT and NSAID
• Mechanism of Action of NSAIDs


  • NSAIDs inhibit synthesis of prostaglandins
  • Cyclooxygenase is the key enzyme in the biosynthesis of prostaglandins
  • COX 1- in all tissues, protective effect smooth muscles, vascular system, gastric secretion reduction
  • COX-2 – present only after tissue injury, promotes inflammation
  • Aspirin, Ibuprofen, Naproxin (Aleve) (first generation NSAIDs) block both COX 1 and COX 2 resulting in decreased inflammation, but blocking COX1 results in SE like bleeding, gastric upset and reduced kidney function
• COX-2 Inhibitors


  • Do not inhibit COX-1, avoiding associated side effects
  • Celecoxib (Celebrex) only one on the market in US due to recall of others
  • Rofecoxib (Vioxx) – doubled risk of heart attack and stroke with extended use- taken off market
  • Baldecoxib (Bextra) –also taken off the market
  • Celbrex also used to reduce colorectal polyps in adults with familial adenomatous polyposis (FAP)
• Fish Oils


  • Omega 3: Two main fatty acids have triglyceride-lowering effect as well as anti-inflammatory
  • Eicosapentaenoic acid (EPA)
  • Docosahexaenoic acid (DHA)