inflammation and wound repair Flashcards
Nomenclature of Inflammatory Diseases
Name of the organ or tissue + “itis”= inflammation in that organ or tissue \
EXCEPTIONS ON HANDOUT
tonsilitis
appendicitis
classification of inflammation
• Acute or chronic inflammation
• Exudative or non-exudative inflammation
• Morphologic Patterns
– Serous
– Fibrinous
– Suppurative
– Ulcerative
acute inflam
onset?
duration?
what cells migrate? predominant type?
what exudates into tissue?
– Rapid onset, short duration (minutes to days)
– Emigration of leukocytes, predominately neutrophils
– Exudation of fluid and plasma proteins
chronic inflam
duration?
cells present?
what can proliferate during this?
– Longer duration
– Mononuclear cells –macrophages, lymphocytes, plasma cells
– Proliferation of blood vessels and fibroblasts
clinical and pathological views of inflamm
neutrophil
plasma cell
macrophage
lymphocyte
acute inflammation, exudative or not?
Exudative - acute inflammation tends to be more exudative, accumulation of fluid
chronic, exudative or not? often associated with?
Non-Exudative - chronic inflammation is frequently non-exudative and is often associated with fibrosis and scarring.
Inflammation
causes?
Inflammation –the body’s response to injury
– Thermal
– Physical
– Chemical
– Allergic
– Immune mediated disease
Immunity
Immunity –comes into play when inflammation is caused by a living organism (infection)
infections can provoke?
inflammation and immunity
• Inflammation may exist without infection
–Inflammation DOES NOT imply infection
Hypersensitivity (allergic disease) may cause
inflammation
Autoimmune disease may cause
Autoimmune disease may cause
inflammation
the body’s 3 defense lines, components of each
• Barriers (non-specific)
– Skin
– Mucous membranes
– Secretions
• Inflammatory Response (non-specific)
– Cells (leukocytes)
– Molecules (mediators)
• Immune Response (specific)
– Antibodies (humoral)
– Cytotoxic T cells (cellular)
Components Of Inflammatory Responses: what cells/proteins have roles?
• Circulating blood cells and plasma proteins
• Cells of the blood vessel walls
• Cells and proteins of the extracellular matrix
where are most inflammatory elements located
blood
inflammation allows for?
means by which defensive cells and chemicals leave the blood and enter the tissue
Inflammation is a complex reaction to injury: what kind of events occur?
– Vascular responses
– Cellular responses
– Systemic reactions
– Repair
Inflammation is good/bad? excessive?
Inflammation is beneficial. Excess or prolonged inflammation may be harmful.
defensive materials delivered by inflammation
• Leukocytes –defensive cells
• Plasma –defensive proteins
The Inflammatory Response: 5 R’s
• Recognition of the injurious agent
• Recruitment of leukocytes
• Removal of the agent
• Regulation (control) of the response
• Resolution (repair)
Causes of Acute Inflammation (types of injuries)
• Mechanical injury
• Chemical injury
• Radiation injury
• Thermal injury
• Infection
• Compromise of blood supply
• Immune injury
Cardinal Signs Inflammation
• Calor –heat
• Rubor - redness
• Tumor - swelling
• Dolor - pain
• Loss of function
is everything red inflamed?
no, can be cell proliferation (hemaghenoma, RBC)
Cellular Events in Acute Inflammation (PMN migration)
mediated by ?
• Margination
• Rolling
• Adhesion
• Diapedesis
• Chemotaxis
• Phagocytosis
• Killing
each step is mediated by dif molecules (selecting, ICAM, integrins, C3b, IgG)
vascular response of inflamm, how does this influence PMN?
vasodilation allowing for PMN margination
Microbial Killing by Leukocytes
opsinization via IgG and C3b
Systemic Manifestations of Acute
Inflammation
fever
leukocytosis
Acute phase response –cytokines stimulate hepatocytes to synthesize and secrete acute phase proteins
Fever due to
due to pyrogens
– Cytokines - TNF, IL-1 released by leukocytes (increased count)
– Prostaglandins –from membrane phospholipids
leukocytosis results
– Leukemoid reaction, can mimic leukiemia
– Neutrophilia - shift-to-left, more than usual
– Lymphocytosis, increased lymphocytes
cytokine stim of hepatocytes
cytokines stimulate hepatocytes to synthesize and secrete acute phase proteins
– C-reactive protein (CRP) –acts as an opsonin
– Mannose-binding lectin - acts as an opsonin
Lymphangitis
lymphatic involvement in inflammation
• Lymphatic spread of bacterial infection
• Painful red streaks and regional lymphadenopathy
preformed chemical mediators stored in granules, cells?
(histamine, serotonin, lyso enzymes)
histamine-mast cell, baso, platelets
serotonin- platelets
lysosomal enzymes- neutrophils and macro
newly synthesized chemical mediators with inflammation, cells?
PGs, LTs, NO, cytokines
PGs- all leuko, platlets, EC
LTs- all leukocytes
NO- macro
cytokines- lymphocytes, macrophages, EC
Hageman factor
from the liver, activated in plasma
activates kinin system (bradykinin) and coagulation and fibrinolysis systems
complement proteins from where, general actions
from the liver
C3a and C5a= anaphylatoxins (neutrophils)
C3b= op
C5a-9= MAC
histamine and serotonin storage
• Unlike most other mediators, histamine and serotonin are available in preformed supplies
• Histamine is stored in granules of mast cells
• Serotonin is stored in the granules of platelets
first mediators released with injury, cause?
Histamine and Serotonin
cause vascular dilation and leakage
Antigen (Ag)
Antigen (Ag) - A substance that can induce an immune response when introduced into an animal.
Antibody (Ab)
Antibody (Ab) - A protein that is produced in response an antigen. The antibody binds the antigen that stimulated its production. All antibodies are immunoglobulins.
Immunoglobulin (Ig)
mmunoglobulin (Ig) - A glycoprotein composed of heavy and light chains that functions as an antibody.
Schematic Structure of a Typical
Immunoglobulin (Antibody) Molecule
IgM
IgM - first immunoglobulin to appear in an immune response
pentamer
IgG
IgG - principal immunoglobulin of the secondary immune response. Only immunoglobulin capable of crossing the placental barrier
IgA
IgA - principal immunoglobulin in external secretions of mucosal surfaces, tears, saliva, and colostrum
dimer
• IgE
• IgE - plays an important role in immediate hypersensitivity reactions and parasitic infections
IgD
IgD - thought to activate the B-lymphocyte
complement a machine for?
perforating cells
The Complement System basics
The Complement System
• C1 to C9
• Critical step activation of C3
–C3 convertase cleaves C3 –C3a, C3b
• C3b deposits to microbes surface, forms C5
convertase
• C5 convertase cleaves C5 –C5a, C5b
• Initiates assembly of MAC
functions of the complement system components
• Membrane attack complex (MAC) lysis
(C56789)
• Opsonization (C3b)
• Chemotaxis (C5a)
• Vasodilation and increased vessel permeability via histamine release
(C3a, C5a) anaphylatoxins
Outcomes of Acute Inflammation
n
- Complete resolution
- Healing by connective tissue replacement (fibrosis)
- Progression of the response to chronic inflammation
resolution of acute inflam
clearance of injurious stimuli
clearance of mediators and inflam cells
replace injured cells
normal function restored
what role does fibrosis play in acute inflam?
healing occurs via fibrosis= loss of function
chronic inflam progression from acute
what events occur?
what cells migrate?
angiogenesis occurs
mononuclear cells infiltrate
fibrosis occurs
serous inflammation
fluid filled= transudate, free of proteins and cells
friction blisters
fibrinous inflammation, example
due to an exudate= protein-rich, often fibrin (fibrinous exudate)
Suppurative (Purulent) Inflammation
pus filled/ protein and cell rich
Suppurative (Purulent) Inflammation
fibrinous inflammation
Abscess
• A localized collection of pus (many dead neutrophils) that has accumulated in a tissue cavity, producing fluctuance
fibrosis around liquefactive necrosis
abcess
abcesses
Cellulitis
Cellulitis
• Diffuse spread of an acute inflammatory process through the fascial planes of soft tissue producing cardinal signs of inflamm without consolidation
Catarrhal (Seromucous) Inflammation
a clinical type of exudative inflammation,
occurs only on mucosal surfaces containing mucus-secreting cells- bronchial mucosa, excess mucus
Ulcerative Inflammation, example?
exudate surrounded with a red halo, defect in epithelial continuity
Recurrent Aphthous Stomatitis
ulcerative inflammation
ulcerative inflammation
Leukocyte Adhesion Deficiency - LAD
inheritence?
what is defective? this leads to impairment of?
susceptible to?
autosomal recessive immune deficiency
due to integrin receptor defect= impaired adhesion and chemotaxis
susceptible to: bac/fungal infections, impaired wound healing, periodontitis (loss of alveolar bone), lack of pus formation
Lazy Leukocyte Syndrome, what is mutated?
Impaired Chemotaxis –Mutation of Contractile Proteins
Chediak-Higashi Syndrome
inheritance?
associated with?
granules?
defective functions?
susceptible to?
plattlets? MPO?
• A rare autosomal recessive condition associated with albinism
• Giant lysosomal inclusions from fused primary granules
• Both chemotaxis and phagolysosome formation are defective
• Recurrent infections, high grade lymphomas
• Platelet function is abnormal, MPO +
PMN of chediak-higahsi
Chronic Granulomatous Disease of Childhood inheritence
X-linked (2/3) or autosomal (1/3)
Chronic Granulomatous Disease of Childhood defect
• Deficient NADPH oxidase in the cell membranes of neutrophils and monocytes, resulting in an absent respiratory burst
• No H2O2 produced - HOCl- is notsynthesized because of the absence of H2O2
Chronic Granulomatous Disease of Childhood organisms capable of infection
• Catalase-negative organisms (e.g., Streptococcus species) are killed
• Catalase-positive organisms (e.g., Staphylococcus aureus) are not killed
catalase able to remove H2O2, thus no respiratory burst
Chronic Granulomatous Disease of Childhood presentation
large granulatomous mass of the face
Chronic Granulomatous Disease of Childhood
Myeloperoxidase (MPO) Deficiency
common?
inheritance?
what is wrong?
• A common (1:2,000 individuals) autosomal recessive absence of myeloperoxidase enzyme in neutrophil and monocyte granules
• Respiratory burst is normal and H2O2 is produced
• Absence of MPO prevents synthesis of HOCl-
clinical consequences of MPO def
• No great clinical consequences in most people
• Diabetics may develop candidiasis
Immune Deficiency Caused by Defects in Leukocyte Function: what are potential defects?
• Too few neutrophils
• Failure in adhesion
• Slow chemotaxis
• Failure to phagocytose
• Failure to kill
Too few neutrophils, Dx?
– Agranulocytosis
– Cyclic neutropenia
Failure in adhesion, Dx?
– Leukocyte Adhesion Deficiency (LAD)
Slow chemotaxis, Dx
– “Lazy” leukocyte syndrome
Failure to phagocytose, dx?
– Bruton Agammaglobulinemia
– Complement deficiency
Failure to kill, Dx?
– Chronic Granulomatous Disease of Childhood
– Chediak-Higashi Syndrome
– Myeloperoxidase Deficiency
Causes of Chronic Inflammation
• Persistent infection - mycobacteria
• Prolonged exposure to toxic agents
• Exogenous - silicosis
• Endogenous - atherosclerosis
• Immune-mediated inflammatory disease
• Autoimmune diseases - rheumatoid arthritis
• Unregulated immune responses against microbes –inflammatory bowel disease
• Immune responses against environmental substances –(allergic disease) -bronchial asthma
Morphologic Features Of Chronic Inflammation
what cells are present?
is tissue destruction occurring? why or why not?
attempts at healing with what processes?
• Mononuclear cell infiltration –lymphocytes, plasma cells and macrophages
• Tissue destruction –due to a persistent offending agent or by the inflammatory cells
• Attempts at healing by connective tissue replacement - angiogenesis and fibrosis
are neutrophils present in chronic inflamm?
yes, but not predominant
is this chronic or acute?
chronic, note Macros, plasma and lymphocytes present= mixed inflammatory infiltrate
Granulomatous Inflammation
acute or chronic?
types?
special kind of chronic inflamm
two kinds: immune granulatomas, foreign body granulatomas
Granulomatous Inflammation morpholgy
Aggregates of epitheliod macrophages (activated) which make the granulatomas
• Multinucleated giant cells
• Mononuclear leukocytes, principally lymphocytes and occasionally plasma cells peripherally
• Fibrosis variable
granulatoma
giant cell macrophage
granulomatous inflammation with surrounding lymphocytes
giant cells
right: foreign body giant cell
left: Langerhans giant cell
Classification of Granulomas
• Immune granulomas
• Foreign body granulomas
immune granuloma
foreign agent trapped within a giant cell: fungi
Caseation Necrosis in Tuberculosis and granulomas
Necrotizing Granulomatous Inflammation will occur with giant cells and granuloma
Mycobacterium Tuberculosis:
Intracellular Pathogen, acid fast bacili
• Blocks fusion of phagosome with lysozome
kinds of granulomatous diseases
Granulation Tissue -VS-Granulomatous Tissue
Granulation Tissue
Reparative Tissue
Endothelial Cells and Fibroblasts
Granulomatous Tissue
Epitheliod Macrophages
Giant Cells
Pyogenic Granuloma: is it granulation tissue or granulomatous tissue
granulation tissue; RBC and fibroblast prolif= endothelial hyperplasia
Repair defined
can occur by?
• Restoration of tissue architecture and function after an injury
• Repair may occur by regeneration or by healing (scar formation)
mechanisms of tissue repair/healing
• Healing –Consists of variable proportions of two distinct processes –regeneration and scarring (fibrosis)
• Regeneration –growth of cells and tissues to replace lost structures
cell classes for regeneration purposes
• Continuously dividing tissues - labile
• Stable tissues - quiescent
• Permanent tissues –non-dividing
Labile cells
Labile cells are derived from?
examples?
• Labile cells are derived from the division of stem cells
• Hematopoietic cells
• Surface epithelium
• Stratified squamous epithelium of the skin, mouth, pharynx, esophagus, vagina and cervix
• Gastrointestinal tract epithelium
labile cells and regeneration
Labile tissues can readily regenerate after injury as long as the pool of stem cells is preserved
labile cells and cancer, examples
The most common forms of cancer arise from labile tissues:
– Epidermis –skin cancer
– Bronchial mucosa –lung cancer
– Oral mucosa –oral cancer
– Cervical mucosa –cervical cancer
– Hematopoietic tissue –leukemias
Quiescent/stable cells
TO rate?
replacement done by?
examples?
• Stable cells are quiescent and have a very low rate of turnover.
• Replacement is carried out by mitotic division of mature cells.
• Viscera (liver, kidney, pancreas)
• Endothelial cells
• Fibroblasts
• Smooth muscle cells
stable cells capacity to regen? exception?
With the exception of liver, stable tissues have limited capacity to regenerate
stable tissues and tumors
Malignant tumors of stable tissues are among the rarer forms of cancer
Permanent Tissues (Non-dividing)
• Permanent cells were generated during fetal life and never divide in postnatal life
• Cannot be replaced if lost
• Neurons
• Cardiac myocytes
repair mech in perm tissues?
In permanent tissues, repair is dominated by scar formation
Fibrosis (Scarring) Occurs If:
–The tissue is intrinsically unable to regenerate (heart, brain)
–The underlying connective tissue scaffolding is disrupted
–Following extensive exudates (organization)
Objectives Of Wound Healing
• Epithelial Regeneration
–Restore integrity of the epithelial surface
• Connective Tissue Repair
–Restore the tensile strength of the sub-epithelial tissue
Healing By Primary Intention
• Healing by primary union occurs when the wound margins are pulled together
all wound healing involves?
inflammatory rxn in absence of infection
Healing By Secondary Intention occur when?
Healing by secondary union occurs when the wound margins are NOT pulled together
Granulation Tissue contents of second intention healing
• Endothelial cells
• Fibroblasts
• Myofibroblasts - contractile
myofibroblasts in second intention
Wound Contraction by Myofibroblasts, bring edges together
Hypertrophic Scar
• Excessive scar formation within the boundaries of the original wound producing a
raised scar
Keloid
demographic?
• Excessive scar formation that grows beyond the boundaries of the original wound
• African-Americans
vitamin C
def? result?
Vitamin C is Required for the Hydroxylation of Proline and Lysine in collagen synthesis, necessary for wound healing
def= scurvy and delayed healing
