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2. Inflammation
• provoked response to tissue injury
• chemical agents
• cold, heat
• trauma
• invasion of microbes
• serves to destroy, dilute or wall off the injurious
agent
• induces repair
• protective response
• can be potentially harmfulwww.indiandentalacademy.com
3. Inflammation
Acute Chronic
Acute versus chronic inflammation are distinguished
by the duration and the type of infiltrating inflammatory cells
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5. Cardinal signs of (acute)
inflammation
• Rubor = redness
• Tumor = swelling
• Calor = heat
• Dolor = pain
(described by Celsus 1st
. Century AD)
• Functio laesa = loss of function
(added by R. Virchow)
Cellulits = acute skin infection commonly
caused by Streptococcus pyogenes or
Staphylococcus aureus
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6. The nomenclature used to describe
inflammation in different tissues employs
the tissue name and the suffix “-itis”
e.g
pancreatitis
meningitis
pericarditis
arthritis
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7. The inflammatory response consists of
a vascular and a cellular reaction
Intensive Care Med. (2004)
30: 1702-1714
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8. Acute inflammation involves:
alteration of vascular caliber
following very brief
vasoconstriction (seconds),
vasodilation leads to increased
blood flow and blood pooling
creating redness and warmth (rubor
and calor)
changes of microvasculature
increased permeability for plasma
proteins and cells creating swelling
(tumor). Fluid loss leads to
concentration of red blood cells and
slowed blood flow (stasis)
emigration of leukocytes from
microcirculation
due to stasis and activation leads
migration towards offending agent
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9. Vascular changes and fluid leakage during acute inflammation lead to
Edema in a process called Exudation
Transudate
•result of hydrostatic
or osmotic imbalance
•ultrafiltrate of plasma
•Low protein content
•specific gravity < 1.015
Exudate
•result of inflammation
•vascular permeability
•high protein content
•specific gravity >1.020
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10. Increased vascular permeability and edema:
a hallmark of acute inflammation
• Leakage is restricted to venules of
20-60µm in diameter
• caused by endothelial gaps
• usually an immediate and transient
response (30 min.)
• Gaps occur due to contraction of
e.g myosin and shortening of the
individual endothelia cell
• loss of protein from plasma leads
to edema
• due to reduced osmotic pressure in the
vasculature
• and increased osmotic pressure in the
interstitium www.indiandentalacademy.com
11. • direct endothelial injury
causing necrotic cell death
will result in leakage from all
levels of microcirculation
(venules, capillaries and
arterioles)
• This reaction is
immediate and
sustained
• Delayed prolonged leakage
begins after 2-12 hours and
can last several days due to
thermal-, x-ray radiation or
ultraviolet radiation (sunburn)
and involves venules and
capillaries
• Leakage from new blood
vessels during tissue repair
(angiogenesis) due to
immature endothelial layer
All these described mechanisms may occur in one
wound (e.g burns) and can be life threateningwww.indiandentalacademy.com
12. Different morphological patterns of acute inflammation can be found
depending on the cause and extend of injury and site of inflammation
Serous inflammation
Fibrinous inflammation
Purulent inflammation
ulcers
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13. A critical function of the vascular inflammatory response (stasis
and vascular permeability) is to deliver leukocytes to the site of
injury in order to clear injurious agents
Neutrophils are commonly the first inflammatory cells (first 6-24 hours) recruited to a
site of inflammation.
Extravasation of leukocytes is a coordinated event of:
margination
rolling,
adhesion,
transmigration (diapedesis)
migration.
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14. In order for leukocytes to leave the vessel lumen, endothelial cells need to be
activated and upregulate adhesion molecules that can interact with
complementary adhesion molecules on leukocytes
Up-regulation of adhesion molecules on endothelial cells is induced by
an array of inflammatory mediators such as TNF, IL-1, histamine and
others produced by tissue resident inflammatory cells.
Selectins Integrins
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15. Four families of adhesion molecules are involved in leukocyte migration
Selectins
E-selectin (on endothelium)
P-selectin (on endothelium &
platelets; is preformed and stored in
Weible Palade bodies)
L-selectin (leukocytes)
Ligands for E-and P-Selectins are
sialylated glycoproteins (e.g
Sialylated Lewis X)
Ligands for L-Selectin are Glycan-
bearing molecules such as
GlyCam-1, CD34, MadCam-1
Immunoglobulin family
ICAM-1 (intercellular
adhesion molecule 1)
VCAM-1 (vascular adhesion
molecule 1)
Are expressed on activated
endothelium
Ligands are integrins on
leukocytes
Integrins (α + β chain)
Heterodimeric molecules
VLA-4 (β1 integrin) binds to
VCAM-1
LFA1 and MAC1
(CD11/CD18) = β2 integrin
bind to ICAM
Expressed on leukocytes
Mucin-like glycoproteins
Heparan sulfate (endothelium)
Ligands for CD44 on
leukocytes
Bind chemokines
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16. Specific targeting of adhesion molecules may be a
promising tool in drug development against some
chronic inflammatory diseases
• e.g Natalizumab, a monoclonal antibody to α4 integrin
chain, blocks the binding of VLA-4 to VCAM-1 on brain-
infiltrating TH-1 cells and the binding of α4β7 integrin to
MadCAM on gut-infiltrating TH-1 cells and has been
successfully used in the treatment of MS and Crohn’s
disease.
( the drug was transiently taken off the market because of safety
concerns, but has recently been re-approved)
• Odulimomab and Efaluzimab are antibodies inhibiting
LFA-1 and have shown promising results in the treatment
of Psoriasis and Graft versus Host disease
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17. Leukocytes follow towards the site of injury
in the tissue along a chemical gradient of
chemo-attractants in a process called
chemotaxis.
Exogenous and endogenous stimuli can act
as chemoattractants
Exogenous: bacterial product (e.g N-
formyl-methionyl peptides
Endogenous: anaphylatoxins (C5a),
leukotrienes (LTB4),
chemokines (e.g IL-8)
Most chemotactic agents signal via G-protein-coupled 7 transmembrane
receptors leading to the activation of phospholipase C resulting in
intracellular Ca2+ release and activation of small GTPases (Rac,Rho,
cdc42). This leads to actin/myosin polymerization and a morphological
response with directional filopodia formation
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18. Wiskott-Aldrich Syndrome:
a defect in the morphological response and
trafficking defect of antigen presenting cells
WAS – Syndrome
Recurrent infections Eczema Thrombocytopenia
Normal leukocytes responding to
chemoattractant
WAS patient leukocyte unable to
respond to chemoattractant
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19. While signaling of chemo-attractants induces a morphological
response and locomotion of neutrophils, pattern recognition
receptors or opsonin receptors induce neutrophil and macrophage
effector functions
Pattern recognition receptors recognize
CD14 LPS
Toll-like receptor endotoxins, CpG, dsRNA,
bacterial proteoglycans
Mannose receptor bacterial carbohydrates
Scavenger receptors lipids
Opsonin-receptors recognize
CR1 complement product C3b
Fcγ receptor IgG coated pathogens
C1q collectins
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20. Neutrophil and macrophage effector functions
serve to eliminate pathogens and noxious
substances
• Phagocytosis of pathogens and noxious
agents
• Release of bactericidal and cytoxic
molecules
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21. Neutrophils are highly motile cells that constitute
the first line of defense of the
innate immune system
Normal neutrophil Phagocytosing neutrophil
They are characterized by a high content of granules in their cytoplasm
which gave them the name granulocytes
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22. Phagocytosis and its outcome involves
three distinct steps
• Recognition and attachment
• Engulfment and fusion of phagosome and
lysosome
• Killing and degradation of ingested material
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23. Neutrophils have oxidative and non-oxidative mechanisms of killing
NADPH oxidase system, a membrane bound enzyme complex, reduces O2 to
superoxide anion (02-), hydrogen peroxide (H2O2), and hydroxyl radical (OH) =
Oxidative burst
H2O-MPO-halide system is thought to be the most efficient bactericidal system (in
vitro!!) by catalyzing the formation of bleach (hypochlorous radical = HOCL.
) from
H2O2 and Cl- which kills bacteria by halogenation or protein and lipid
peroxidation
Bacteriocidal and cell degrading enzyme contents of lysosomal granules
(azurophil- and specific granules) fuse with phagosome to form phago-lysosome
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24. Oxidative burst and co-lateral damage
The NADPH oxidase system is only active when the cytosolic subunits are
assembled with the membrane bound subunits in response to leukocyte
activation.
Inflammatory products may be released into the extracellular space causing
tissue damage and additional disease.
Release occurs transiently during “engulfing” = regurgitation during feeding
If material is deposited on flat membranes and can not be removed (e.g immune
complexes on basement membrane) = frustrated phagocytosis
Ingestion of membranolytic material (urate crystals)
phagocytosis
Oxidative burst
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25. Immunodeficiency Diseases caused by deficiencies or
defects in phagocytes (neutrophils and macrophages)
Lack of neutrophil/macrophage numbers or defect of their
function can lead to live threatening infectious diseases,
particularly with bacterial and fungal pathogens
Clinically most common:
bone marrow suppression with decreased cell numbers
(leukopenia) due to tumor infiltrate or chemotherapy resulting in
myelosuppression (>500 neutrophils /µl is considered very
severe)
However, inherited defects of adhesion, phago-lysosome- and
microbicidal functions have been found
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26. Leukocyte adhesion deficiency 1 and 2
(LAD1/2)
LAD 1 is a result of a lack of β2 intergrin expression due
to defect of CD18 (LFA-1 and MAC-1). Interaction with
ICAM and VCAM on endothelium is impaired
LAD 2 results from a lack of sialyl LewisX (defect of
carbohydrate fucosylation). Interaction with endothelial
E-and P-selectins is impaired
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27. Leukocyte adhesion deficiencies (LAD 1 and 2)
Neutrophils unable to aggregate
Leukocytes unable to leave the circulatory
system
Neutrophil counts are commonly twice
the normal level even without
an ongoing infection
(Leukocytosis)
Clinical findings:
History of delayed separation of umbilical cord
Severe peridontitis
Recurrent bacterial and fungal infections of oral
and genital mucosa (enteric bacteria, staph,
candida, aspergillus)
Infected foci contain few neutrophils (no pus) and
heal poorly
LAD 2 immunodeficiency is less severe, however the defect is associated with
growth retardation, dysmorphy and neurological deficits
NEJM:Vol.343:No23,pp1703-1714
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28. Chronic granulomatous disease
(a defect of NADPH oxidase system and therefore inability to
undergo oxidative burst and production of hydrogen peroxide)
• CGD is a heterogeneous
disorder caused by defects
of any of the four subunits
of NADPH oxidase.
• 70% are due to X-linked
defect of gp91 phox (more
severe form)
• Second most due to
autosomal recessive
defect of p47 phox
NEJM: Vol. 343: No 23, pp1703-1714www.indiandentalacademy.com
29. Chronic granulomatous disease = defect of NADPH oxidase system
Clinical findings:
Recurrent infections with catalse-
positve microorganisms
(S. aureus, Burgholderia cepacia,
Aspergillus spec., Nocardia spec., and
Serratia marrcescens)
Recurrent infections of lungs, soft
tissue and other organs (typical is
infection of nares, and gingivitis)
Fever and other clinical signs of
infection may be delayed
Excessive formation of granuloma in
all tissues
NEJM: Vol. 343: No 23, pp1703-1714www.indiandentalacademy.com
30. Chediak-Higashi Syndrome
Defect of the formation and function of neutrophil
granules
CHS is an autosomal recessive disorder of all lysosomal granule
containing cells with clinical features involving the hematological and
neurological system
• All cells containing lysosomes have giant granules.
• In neutrophils large granules result from abnormal fusion of
azurophilic and specific granules and delayed fusion with
phagosomes.
• Neutrophils of CHS patients fail to orient themselves during
chemotaxis resulting in delayed diapedesis
• Mutated gene: LYST = protein involved in vacuolar formation and
transport of proteins
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31. Defect of the formation and function of neutrophil granules
Chediak-Higashi Syndrome
Clinical features:
recurrent bacterial infections
with S. aureus and beta hemolytic
streptoc.;
Peripheral nerve defects
(nystagmus and neuropathy)
Mild mental retardation and partial
ocular and cutaneous albinism
Platelet dysfunction and severe
periodontal disease
Mild neutropenia and normal
immunoglobulins
NEJM: Vol. 343: No 23, pp1703-1714
Normal PMN Abnormal PMN
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32. Myeloperoxidase deficiency
• Most common inherited
disorder of neutrophils
• Catalyzes the generation of
hypochlorous acid (HOCL)
• A deficiency is not generally
associated with disease(!!!!)
• Except in patients with
diabetes mellitus, who are
susceptible to disseminated
Candidiasis
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33. Acute Inflammation 2
chemical mediators, outcome and termination
Nicole Meissner-Pearson
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34. The inflammatory response consists of two main components:
a vascular and a cellular reaction
IntensiveCareMed.(2004)
30:1702-1714
www.indiandentalacademy.com
35. Mediators of acute inflammation
Effector-cell-derived factors
preformed in secretory granules:
Mast cell Neutrophil/Macrophage Platelet
Histamine Lysosomal enzymes Serotonin
Newly synthesized
Prostaglandins
Leukotrienes
Platelet activating factor
Oxygen radicals
NO
cytokineswww.indiandentalacademy.com
36. Mediators of acute inflammation
Plasma factors synthesized mainly in liver
Plasma proteins
Factor XII =
coagulation system
(Hageman factor)
activation
Kinin system
Coagulation
system
Complement
activation
C3a
C5a
C3b
C5b-C9
anaphylatoxins
opsonin
MAC
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37. Histamine and Serotonin
induce vasodilation and increased vascular
permeability
Mast cell :
• richest source of histamine
• located in connective tissue
• adjacent to blood vessels
• Degranulation through receptors for IgE-,
IgG, histamine, bacterial products and
anaphylatoxin C5a, physical injury, cold,
heat
• release of PAF (platelet activating factor)
leads to serotonin and histamine release
from activated platelets
• Mastcells are very important effector cells
in hypersensitivity reactions (anaphylactic
reactions)
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38. Further mediator release by mast cells perpetuates acute
inflammation at the site of release
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39. Histamine receptors
H2 blockers more relevant
in gastric ulcer treatment
H1 blockers are used to treat
allergic and inflammatory
reactions
H1 receptors are found on smooth muscles of intestines, blood vessels and bronchi
H2 receptors are found in gastric parietal cells, vasculature and central nervous system
H3 receptors are found in brain www.indiandentalacademy.com
40. Metabolites of Arachidonic Acid (eicosanoids)
•Membrane lipids of activated cells can be transformed
into biological active lipid mediators
•All mammalian cells except erythrocytes can produce
eicosanoids
•They are autocoids = short-range hormones (very
short range and half-life)
• Arachidonic acid is derived from conversion of
linoleic acid
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42. Distinct Prostaglandins and Leukotrienes are derived by the
action of specific enzymes on an intermediate in the pathway and
some of these enzymes have restricted tissue distribution
*
*5-hydroxyperoxyeicosatetraenoic acids
(+) refers to vasoconstriction, (-) refers to vasodilationwww.indiandentalacademy.com
44. SteroidsX
X
Lipoxigenase inhibitors
XLeukotriene
receptor
antagonists
Therapeutic intervention in arachidonic acid
metabolism and mediator action
Predominantly
Cox-1
Predominantly
Cox-2
Coxibs = selective Cox-2 inhibitors
Aspirin suppresses Cox-1 10-100 X more than Cox-2
*5-hydroxyperoxyeicosatetraenoic acids
(+) refers to vasoconstriction, (-) refers to vasodilationwww.indiandentalacademy.com
45. Nitric Oxide (NO)
a pleitropic mediator of inflammation
NO was initially discovered as
endothelium derived
relaxing factor
NO is a soluble gas
NO is produce by many cells
including:
1. endothelial cells
2. some neurons
3. phagocytes
synthesized from L-arginine by:
nitric oxide synthase (NOS)
Three different NOS:
endothelial eNOS
neuronal nNOS
inducible iNOS
(phagocytes)
Constitutive
expression
*
* peroxynitrate www.indiandentalacademy.com
46. NO modulates the inflammatory
response
• NO is a potent vasodilator
• Reduces platelet aggregation
• Reduces leukocyte recruitment
• Is antimicrobial
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47. Inhaled Nitric Oxide in the treatment of Persistent
Pulmonary Hypertension of the Newborn (PPHN)
PPHN is caused by the persistence of fetal circulation after birth with right to left
shunting of blood through fetal channels (foramen ovale and ductus ateriosus)
secondary to elevated pulmonary vascular resistance and consequently reduction of
pulmonary blood flow
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48. Inhaled Nitric Oxide in the treatment of Persistent
Pulmonary Hypertension of the Newborn
• Inhaled NO relaxes
pulmonary vessels
and thereby decreases
pulmonary vascular
resistance
• This selectivity is the
result of rapid
hemoglobin-mediated
inactivation
• Pulmonary blood flow
is increased and right
ventricular afterload is
reduced
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49. Kinin-Bradykinin System
(HMWK)
Bradykinin increases vascular permeability, contraction of smooth
muscles, vasodilation and pain
Kallikrein is a potent activator of factor XII, is chemotactic and can
directly convert C5 to C5a
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50. Coagulation system
a cascade of serine proteases
Thrombin provides the main link between
coagulation and inflammation by binding
to protease activated receptors (PARs) on
platelets, endothelium and smooth muscle
and leukocytes
PAR-signaling induces:
Chemokines
Endothelial adhesion
molecules (ICAM, VCAM)
P selectin mobilization
from Weibel Palade bodies
COX-2
PAF
NO
plasminogen
plasmin
Fibrinolysis
Fibrin split products
Hageman fact.
Thrombin Fact. IIa
Intrinsic pathway
Extrinsic pathway
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56. TNF and IL-1 (and IL-6)
two macrophage derived cytokines mediating
inflammation
Action:
•Activation of endothelium
•Priming of neutrophils
•Stimulation of
inflammatory mediator
release
•Induction of systemic
acute phase response
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57. Systemic effects of acute inflammation
acute phase response
• Fever (temperature > 37.8o
C or >100 F)
• Increased pulse, blood pressure
• Chills
• Anorexia
• Leukocytosis
• Neutrophilia and left shift of neutrophils points to bacterial
infection
• Lymphocytosis points to viral infection
• Eosinophilia point to allergy or parasitic infection
• Acute phase protein production in liver
• fibrinogen, CRP,SAA leads to increased ESR
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59. Increased Erythrocyte Sedimentation Rate as a
result of the presence of acute phase reactants
ESR = rate at which erythrocytes settle
out of unclotted blood in one hour
Normally, Erythrocytes are very
buoyant and settle slowly
Erythrocytes are negatively charged
and repel each other (no aggregation
occurs)
In presence of acute phase reactants
(fibrinogen) erythrocytes aggregate
due to loss of their negative charge
resulting in increased sedimentation
ESR is a widely performed test to detect occult processes and
monitor inflammatory conditions
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60. Granulocytosis with “left shift” of neutrophil population are a
good indicator for a severe bacterial infection
Leukocyte release results from a direct effect of IL-1 and IL-6 on bone
marrow neutrophil stores.
Exaggeration of this can result in a “Leukemoid reaction” release of
very immature precursors and cell counts >25-30 x 106
/µl
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61. Termination of acute inflammation
• Eradication of an offending agent should lead to
discontinuation of the inflammatory response
• Neutrophils have only a short life span (few hours -1 day)
• Most mediators are very short lived and are degraded
immediately
• Anti-inflammatory cytokines (TGF-beta, and IL-10) can inhibit
the production of pro-inflammatory cytokines (TNF)
• In Arachidonic acid metabolism, lipoxin and resolvins are
generated that have anti-inflammatory activity
However, the exact mechanisms by which acute
inflammation resolves remain still somewhat elusive
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62. Lipoxins are generated from
Arachidonic acid (AA)-metabolites
Resolvins are generated from
Omega-3 poly unsaturated
fatty acids
Once leukocytes enter tissue they gradually
Switch their lipoxygenase-derived AA-mediators
from proinflammatory to anti-inflammatory
mediators
Nature Immunology 2005
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63. Outcome of acute inflammation
• Complete restitution
• Abscess formation (encapsulation and
pus)
• Chronic inflammation
• Healing with scar formation
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64. Examples of acute inflammatory diseases of
different origin
• Allergic reaction
• Bacterial pneumonia
• Peptic ulcer
• Sepsis
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65. Allergic Reaction with swelling of the larynx
Or mucosa
Asthma symptoms
when affecting the lung
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66. Pneumonia = infection of the lung
• Most community acquired
Pneumonias are bacterial of
origin
• Often the infection follows a viral
upper respiratory tract infection
• Acute bacterial pneumonias
present as two anatomical
patterns:
– Bronchopneumonia
– Lobar pneumonia
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67. What causes the white consolidation of the
Chest-X-ray?
Normal lung
histology
Congested septal
capillaries
Extensive erythrocyte,
neutrophil and
fibrin exudation
Pneumonia
= red hepatization
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68. Pathological Stages of Lobar Pneumonia
• Congestion
– Lung is heavy and red due to vascular engorgement and intra-
alveolar fluid with few neutrophils
• Red Hepatization
– Massive confluent exudation with red cells, neutrophils and fibrin
into alveolar spaces
– Lobes are distinctly red, firm and airless, with liver-like consistency
• Gray Hepatization
– Follows with progressive disintegration of red cells and persistence
of a fibrino-suppurative exudate resulting in grayish dry
appearance
• Resolution or scarring
– Resolution due to clearance of the infection and enzymatic digest
of exudate which can be reabosrbed, ingested by macrophages
cleared via muco-cilliary escalator
– Scarring due to organization of exudate, infiltration of fibroblasts
and deposition of collagen
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70. Abscess formation
• is the result of a suppurative (purulent)
necrosis of the parechyma resulting in
the formation of one or more cavities
• it has a central necrosis, rimmed by
neutrophils and surrounded by
fibroblasts
Occurs in the lung due to:
• Aspiration of infective material
• Aspiration of gastric content
• Complication of necrotizing bacterial
pneumonia (e.g Staphylococcus)
• Septic embolism
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71. Peptic ulcer
An ulcer is a local defect of
mucosal lining produced by
shedding of necrotic tissue
Peptic ulcers are produced by an
imbalance between gastro-
duodenal defense mechanisms
and the damaging force
70% of all ulcers are due to H.
pyolri infection which initiates a
strong inflammatory response
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72. Septicemia with disseminated intravascular
coagulation due to Meningococcal Infection
Invasion of the bloodstream by Neisseria meningitides leads to
widespread vascular injury with endothelial necrosis, thrombosis
and peri-vascular hemorrhage.
Hemorrhage as it is seen in the skin can occur in all organswww.indiandentalacademy.com