Injury, Inflammation,

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Injury, Inflammation, Repair

• Mark A. Merrick, PhD, ATC
• Director, Athletic Training Division
• The Ohio State University

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Overview

• Types of Injury
• Acute Inflammation
• Soft Tissue Repair
• Chronic Inflammation
• Phases of Healing
• Clinical Applications

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Types of Injury

• Primary Injury
• The initial, immediate trauma associated with an
  injury
• Many Causes
• Physical / Mechanical
• Metabolic (hypoxia)
• Thermal
• Biological (infections)
• Chemical
• Nothing we can do to limit after the fact

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Types of Injury

• Secondary Injury
• Additional injury that occurs as a result of the
  primary injury

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Secondary Injury

• Two types
• secondary enzymatic
• secondary hypoxic (better called secondary
  ischemic)
• Affects uninjured cells on periphery of the
  primary lesion
• Increases total quantity of tissue damage
• potentially increases healing time

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Secondary Injury Knights Model
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Secondary Enzymatic Injury

• Lysosomes release enzymes
• enzymes not specifically identified
• phospholipases acid hydrolases?
• Enzymes damage surrounding cells
• cleave hydrocarbon chains from membrane
  phospholipids
• Cell Membrane loses integrity polarity
• Hydropic Swelling..Cell death

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Secondary Hypoxic Injury

• Knight thought this more important
• Vascular Inflammatory Changes cause a period
  of hypoxia
• Causes a shift to anaerobic metabolism
• Eventual inability to produce adequate ATP
• Failure of membrane ion pumps
• Hydropic swelling..Cell Death

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Where does hypoxia come from?

• Damaged Blood Vessels
• Hemostasis / Clotting
• Inflammation induced hemoconcentration
• thicker blood does not flow as well
• Increased extravascular pressure from expanding
  hematoma
• Pain induced muscle spasm
• Hydropic swelling of injured cells

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Hypoxia v. Ischemia

• Knight suggests hypoxia (inadequate oxygen) is
  the problem, but ischemia (inadequate blood flow)
  is probably more correct.
• Ischemia causes 3 physiologic problems
• hypoxia
• inadequate supply of nutrients (e.g. glucose)
• inadequate removal of waste

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Secondary Ischemic Injury

• Ischemia
• similar mechanisms to hypoxia
• injury generally occurs sooner than with hypoxia
  alone
• loss of membrane integrity and ion pumps
• influx of Ca2 and other ions
• mitochondrial swelling and cellular swelling
• cell death

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Overview

• Types of Injury
• Acute Inflammation
• Soft Tissue Repair
• Chronic Inflammation
• Phases of Healing
• Clinical Applications

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Acute Inflammation

• What is it?
• Series of reactions of vascularized tissue to
  injury
• What is its purpose?
• Defend against foreign substances (infection)
• Dispose of dead / dying tissue
• Immobilize injured area
• Compartmentalize area

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Acute Inflammation

• Events in Acute Inflammation
• Neurologic events
• Hemodynamic events
• Cellular events
• Events Overlap and are related
• Events are the same regardless of cause of
  inflammation
• Magnitude of events depends on
• severity of injury
• immune status
• temperature

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Acute Inflammation Neurologic events

• Initial Vasoconstriction
• Transatory reflexive
• usually lasts up to 30 seconds
• Gradual Vasodilation
• Relaxation of reflexive spasm
• Causes bleeding to start

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Acute Inflammation Hemodynamic events

• Vasodilation
• From relaxation of reflex chemical mediators
• Slowing of bloodflow
• Relationship of flow to diameter
• Margination of Leukocytes
• ???? Nobel prize for Medicine
• Hemostasis
• Permeability Changes

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Acute Inflammation Hemodynamic events

• Permeability Changes
• Mostly from inflammatory chemicals
• Occurs in capillaries small venules
• Junctions between epithelial cells loosen
• Fluid leaks (transudate exudate)
• Leads to hemoconcentration
• Makes margination easier

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Acute Inflammation Cellular Events

• Mast Cells
• Already present in connective tissue
• Damage to connective tissue leads to activation
  degranulation
• Release histamine (increases vasodilation
  permeability)
• Release heparin (anticoagulant)

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Acute Inflammation Cellular Events

• Circulating Leukocytes
• Marginated cells emmigrate from vasculature
  (diapedesis) smaller first, larger later
• Basophils release anti-coagulants
• Neutrophils vicious phagocytes
• Release many chemical mediators chemotaxis
• Primary job is to phagocytize bacteria
• Magnifies inflammation above required level in
  musculoskeletal injury
• Monocytes Macrophages
• Arrive 5h post-injury
• Remove dead tissue debris (clean up the mess)

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Acute Inflammation Chemical events

• Over 180 different chemicals involved in acute
  inflammation
• Sources damaged cells, inflammatory cells,
  platelets, plasma, etc.
• Histamine 1st chemical, strong vasodilator
  increases permeability
• Bradykinins increases permeability pain
  (especially with prostaglandins)
• Prostaglandins made from released phospholipids
  (arachadonic acid cascade)
• Target of NSAIDS steroidal anti-inflammatories

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Inflammatory Process
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Acute Inflammation big picture

• First few seconds
• Immediate vasoconstriction
• First Hour
• Gradual vasodilation
• Hemostasis begins
• Mast Cell degranulation
• Margination of WBCs
• Large scale neutrophil response begins

• After the first hour?
• Hemoconcentration from edema
• Ischemia
• Growing interaction of chemical mediators
• Emmigration of larger WBCs
• Complement System

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Acute Inflammation

• Post- Acute Inflammation (Chronic inflammation?)
• Clinicians Immunologists differ on terminology
• Follows acute phase response if tissue is damaged
• Characterized by macrophages, lymphocytes (CD8,
  CD4)

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Overview

• Types of Injury
• Acute Inflammation
• Soft Tissue Repair
• Chronic Inflammation
• Phases of Healing
• Clinical Applications

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Post-Acute Inflammation

• Processes depend on level of damage
• Resolution if little or no damage
• Inflammation resolves, return to competition
• Repair regeneration if meaningful damage
• Regeneration replacement with the same kind of
  tissue (depends on tissue)
• Labile fully regenerates (e.g. epithelium)
• Stabile partially regenerates (e.g. bone)
• Permanent does not regenerate (e.g. muscle)

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Tissue Repair

• Fibroplasia fibrous repair
• Formulation of Granulation tissue
• Capillary budding results from mitogens
• PDGF most important, hypoxia contributes
• Forms meshlike framework for scar development
• Infiltration of fibroblasts
• Collagen laid down in random pattern
• Structure can be manipulated!!!!!
• Scar tissues excessive if inflammation
  re-initiated

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Tissue Repair

• Maturation Remodeling
• Initial scar formation takes weeks
• Scar matures
• Longest part of inflammation (over 1 yr)
• Re-absorb temporary vasculature
• Scar shrinks (contraction) changes color
• Scar remodels
• Collagen fibers re-align with stress (SAID)
• Less tensile strength than tissue it replaces

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Overview

• Types of Injury
• Acute Inflammation
• Soft Tissue Repair
• Chronic Inflammation
• Phases of Healing
• Clinical Applications

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Chronic Inflammation

• Immunologists define as period when macrophages
  predominate
• Clinicians define as recurrent inflammation prior
  to completion of repair or resolution
• Cellular Aspects
• Leukocytes during early post-acute phase
• CD8 (T- killer) CD4 (delayed hypersensitivity)

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Chronic Inflammation

• Easy to re-start inflammation
• Clinically, must control activity level protect
  injury site
• Leads to hypertrophic scarring
• Additional infiltration of fibroblasts
• Abundance of stimulating chemicals