Acute inflammation pathophysiology

1. Acute and Chronic
Inflammation
CHEGE.B.M
Lecturer/Medical Physiologist

2. Learning objectives
• Definition
• Introduction
• Cellular events
• Vascular events
• Patterns including suppurative
• Outcomes

3. Acute Inflammation

4. Definition
• Inflammation is a response of vascularized
tissues to infections and tissue damage that
brings cells and molecules of host defense
from the circulation to the sites where they are
needed, to eliminate the offending agents
• Rapid host response that serves to deliver
leucocytes and plasma proteins such as
antibodies to sites of infection or tissue
injury.

5. Inflammation is a war
• Coordinated response to eliminate the cause
and consequence of injury or infection
(noxious agent)
• Involves immune (cellular events) and
vascular systems (Vascular events)

6. Inflammatory process
• Inflammation
• Purpose is 3 d’s:
 Destroy
 Dilute
 Dam-off
• Desired result is healing
 Regeneration (hyperplasia)
 Fibrosis (scarring)
• Collateral damage may occur

7. CARDINAL SIGNS OF INFLAMMATION
Rubor (redness)
Tumor (swelling)
Calor (heat)
Dolor (pain)
Functio laesa (loss of function)

8. Inflammatory stimuli
Infective agents like bacteria, viruses and their toxins, fungi,
parasites
Immunological agents like cell-mediated and antigen-antibody
reactions
Physical agents like heat, cold, radiation, mechanical trauma
Chemical agents like organic and inorganic poisons
Inert materials such as foreign bodies

9. The typical inflammatory reaction develops through a
series of sequential steps:
• The offending agent, which is located in extravascular
tissues, is recognized by host cells and molecules.
• Leukocytes and plasma proteins are recruited from the
circulation to the site where the offending agent is located.
• The leukocytes and proteins are activated and work
together to destroy and eliminate the offending substance.
• The reaction is controlled and terminated.
• The damaged tissue is repaired.

12. Types of Inflammation
Inflammation may be of two
types,
 Acute inflammation
 Chronic inflammation

13. Acute Inflammation
• The initial, rapid response to infections and tissue
damage is called acute inflammation.
• It typically develops within minutes or hours and is of
short duration, lasting for several hours or a few days.
• Acute inflammation is a stereotyped response (unlearned behavioral reaction of an organism to some environmental
stimulus)to recent or ongoing injury
Chronic Inflammation
• If the initial response fails to clear the stimulus, the
reaction progresses to a protracted type of
inflammation that is called chronic inflammation.
• Chronic inflammation may follow acute inflammation
or arise de novo (From beginning).
• It is of longer duration and is associated with more
tissue destruction, the presence of lymphocytes and
macrophages, the proliferation of blood vessels, and
fibrosis.

14. ACUTE INFLAMMATION
Acute inflammation has three major
components:
(1) dilation of small vessels, leading to an
increase in blood flow,
(2) increased permeability of the
microvasculature, enabling plasma proteins and
leukocytes to leave the circulation, and
(3) emigration of the leukocytes from the
microcirculation, their accumulation in the focus
of
injury, and their activation to eliminate the
offending
agent

15. Reactions of Blood Vessels in Acute
inflammation
(Acute Vascular Changes)
• The vascular reactions of acute
inflammation consist of changes in the flow
of blood and the permeability of vessels,
both designed to maximize the movement
of plasma proteins and leukocytes out of
the circulation and into the site of infection
or injury.
• Definitions
• An exudate?
• Transudate?
• Edema?

16. Acute vascular changes
• Transient arteriolar constriction (seconds)
• Nerve reflex, endothelin
• Like the immediate first step of hemostasis
• Vasodilation of arterioles (until resolution)
• Histamine, bradykinin mediate rapid response
• Sustained by prostaglandins and NO
• Hyperemia, erythema
• Transudation increases blood viscosity, slows flow
• Stasis and congestion in venules allows cells to contact
endothelium
• Vascular leakage (minutes to hours to days)
• Histamine, bradykinin mediate rapid response
• Sustained by C3a, C5a, PAF, leukotrienes
• Exudation results in local edema

18. Increased vascular permeability
• Contraction of vascular endothelium—rounding
of cells and widening of intercellular spaces
 Immediate, transient response (15-30 min)
• Stimulated by histamine, bradykinin, substance P
• venules of 20 – 60 um diameter respond
 Delayed prolonged leakage (radiation burns)
• begins after 2 – 12 h delay, lasts hours – days
• stimulated by cytokines and apoptotsis of injured skin cells
• venules and capillaries respond
 Immediate, sustained response (days)
• caused by direct damage to vasular endothelium
• venules, capillaries, arterioles respond
• ended by hemostasis, thrombosis, regeneration
 Neutrophil-induced damage (days)
• caused when neutrophils adhere and emigrate

19. Leukocyte extravasation
• Margination, rolling
• Decreased flow rate and volume push WBCs
toward vascular walls
• Intermittent binding of selectins with glycoproteins
causes rolling
• Adhesion, pavementing
• mediated by integrins on leukocytes, activated by
cytokines
• integrin ligands VCAM-1, ICAM-1 on endothelial
cells induced by TNF and IL-1
• Transmigration or diapedesis
• chemokines stimulate adherent leukocytes to
migrate through interendothelial spaces

20. • The journey of leukocytes from the vessel lumen to
the tissue is a multistep process that is mediated
and controlled by adhesion molecules and
cytokines.
• This process can be divided into phases, consisting
first of adhesion of leukocytes to endothelium at
the site of inflammation, then transmigration of
the leukocytes through the vessel wall, and
movement of the cells toward the offending
agent.

21. Leukocyte Adhesion to
Endothelium
• Normally, Leukocytes are pushed out toward
the wall of the vessel, but the flow prevents the
cells from attaching to the endothelium
• As the blood flow slows early in inflammation
(stasis), hemodynamic conditions change (wall
shear stress decreases),and more white cells
assume a peripheral position along the
endothelial surface. This process of leukocyte
redistribution is called margination.

22. • By moving close to the vessel wall, leukocytes are
able to detect and react to changes in the
endothelium. If the endothelial cells are activated by
cytokines and other mediators produced locally, they
express adhesion molecules to which the leukocytes
attach loosely.
• These cells bind and detach and thus begin to tumble
‘somersaults’ on the endothelial surface, a process
called rolling.
• The cells finally come to rest at some point where
they adhere firmly (resembling pebbles over which a
stream runs without disturbing them).

23. • The attachment of leukocytes to endothelial
cells is mediated by complementary adhesion
molecules on the two cell types whose
expression is enhanced by cytokines.
• The two major families of molecules involved in
leukocyte adhesion and migration are the
selectins and integrins.
• These molecules are expressed on leukocytes
and endothelial cells, as are their ligands.
• Selectins mediate the initial weak
interactions between leukocytes and
endothelium.
• Firm adhesion of leukocytes to endothelium
is mediated by a family of leukocyte surface

24. Leukocyte Migration Through
Endothelium
• After being arrested on the endothelial surface,
leukocytes migrate through the vessel wall
primarily by squeezing between cells at
intercellular junctions
• This extravasation of leukocytes, called
transmigration, occurs mainly in postcapillary
venules, the site at which there is maximal
retraction of endothelial cells
 Further movement of leukocytes is driven by
chemokines produced in extravascular tissues,
which stimulate leukocytes to travel along a
chemical gradient

25. • After traversing the endothelium, leukocytes
pierce the basement membrane, probably by
secreting collagenases, and they enter the
extravascular tissue.
• Typically, the vessel wall is not injured during
leukocyte transmigration

26. Chemotaxis of Leukocytes
• After exiting the circulation, leukocytes move in the
tissues toward the site of injury by a process called
chemotaxis.
• Chemotaxis :is defined as locomotion along a
chemical gradient.
• Both exogenous and endogenous substances can act
as chemoattractants, including the following:
• Bacterial products, particularly peptides with
Nformylmethionine
termini
• Cytokines, especially those of the chemokine family
• Components of the complement system, particularly C5a
• Products of the lipoxygenase pathway of arachidonic
acid (AA) metabolism, particularly leukotriene B4 (LTB4)
NB: These chemoattractants are produced by microbes
and by host cells in response to infections and tissue
damage and during immunologic reactions.

27. Which types of leukocytes respond
• Neutrophils are generally the first types of leukocytes to
respond in acute (non-viral) inflammation or to necrosis
• Lymphocytes are usually the first cells to respond to viral
infections or autoimmune diseases
 lymphocytes and plasma cells also participate in most chronic
inflammation, regardless of the inciting cause
• Macrophages begin to appear a few days after the onset
of inflammation from almost any cause, and increase in
numbers over time
 activated macrophages may develop abundant cytoplasm, called
epithelioid macrophage
 macrophages merge to create giant cells with multiple nuclei
• Eosinophilic inflammation is highly suggestive of a
response to helminths, arthropods, or allergens

28. Acute inflammation
• Immediate, early response
 Vasodilation
 Vascular permeability
 Emigration of leukocytes into tissues
• Reactions of leukocytes in inflammation
 Recognition of microbes and dead tissues
 Removal of the offending agents
 Macrophage activation
 Leukocyte-mediated tissue injury

29. Actions of activated neutrophils
• Recognition of microbes or dead cells induces several responses in leukocytes that are
collectively called leukocyte activation
• The Leukocytes must be activated to perform their functions.
• Phagocytosis has three steps
 recognition and attachment of the particle to
be ingested
 engulfment, with subsequent formation of a
phagocytic vacuole
 killing or degradation of the ingested material
• Initiation of repair
 stimulate the proliferation of endothelial cells
and fibroblasts
 stimulate synthesis of collagen and enzymes
that remodel connective tissues

31. • Several types of inflammation vary in their
morphology and clinical correlates.
• Why?
 The severity of the reaction
 specific cause
 the particular tissue
 site involved
Morphologic Patterns of Acute
Inflammation

32. Morphologic Patterns of Acute
Inflammation
• serous inflammation
• fibrinous inflammation
• suppurative or purulent inflammation
• ulcers

33. Patterns of Acute Inflammation
• SEROUS INFLAMMATION:
 Serous inflammation is marked by the
outpouring of a thin fluid
 e.g. the skin blister resulting from a burn or
viral infection represents a large accumulation
of serous fluid

36. • FIBRINOUS INFLAMMATION
 more severe injuries and more greater
vascular permeability, larger molecules such
as fibrinogen pass the vascular barrier, and
fibrin is formed and deposited
Morphologic Patterns of Acute Inflammation

37.  A fibrinous exudate is characteristic of
inflammation in the lining of body cavities, such as
the meninges, pericardium and pleura
 Bread and butter apperance
Morphologic Patterns of Acute
Inflammation
FIBRINOUS INFLAMMATION

38. • FIBRINOUS INFLAMMATION
 Fibrinous exudates may be removed by
fibrinolysis
 But when the fibrin is not removed, it may
stimulate the ingrowth of fibroblasts and blood
vessels and thus lead to scarring
Morphologic Patterns of Acute Inflammation

39. SUPPURATIVE OR PURULENT INFLAMMATION
 characterized by the production of large
amounts of pus or purulent exudate
consisting of neutrophils, necrotic cells,
and edema fluid
 Certain bacteria (e.g., staphylococci)
produce this localized suppuration and are
therefore referred to as pyogenic (pus-
producing) bacteria
Morphologic Patterns of Acute Inflammation,

40. Suppurative inflammation. A, A subcutaneous bacterial abscess with
collections of pus. B, The abscess contains neutrophils, edema fluid, and
cellular debris.

41. Purulent inflammation

42.  Abscesses : localized collections of
purulent inflammatory tissue caused by
suppuration buried in a tissue, an organ,
or a confined space
SUPPURATIVE OR PURULENT INFLAMMATION

43. Brain Abscess

44. Liver abscess

45. Localized liquefactive necrosis liver abscess
Removal of the
dead tissue
leaves behind a
scar

46. Morphologic Patterns of Acute
Inflammation –
ULCERS
 An ulcer is a local defect of the surface of an
organ or tissue that is produced by the
sloughing (shedding) of inflammatory necrotic
tissue

47. ULCERS
encountered in:
1) inflammatory necrosis of the mucosa of the
mouth, stomach, intestines, or genitourinary
tract
2) subcutaneous inflammation of the lower
extremities in older persons who have
circulatory disturbances
Morphologic Patterns of Acute
Inflammation

48. Ulceration can occur only when tissue necrosis and
resultant inflammation exist on or near a surface
Epithelial Defect
Fibrinopurulent exudates
Granulation tissue
Fibrosis
Necrotic base

49. Termination of acute response
• Inflammation declines spontaneously
 Mediators of inflammation are produced in rapid bursts only
while the stimulus persists
 Mediators have short half-lives and are degraded after their
release.
 Neutrophils also have short half-lives in tissues and die by
apoptosis within a few hours after leaving the blood
• Active termination mechanisms include
 Switch from pro-inflammatory leukotrienes to anti-inflammatory
lipoxins
 Release of anti-inflammatory cytokines, including transforming
growth factor-β (TGF-β) and IL-10, from macrophages
 production of anti-inflammatory lipid mediators, called resolvins
and protectins, derived from polyunsaturated fatty acids
 neural impulses (cholinergic discharge) that inhibit the
production of TNF in macrophages

50. Arachidonic Acid Pathway
https://www.youtube.com/watch?v=gnz841lGa7Q

51. Arachidonic Acid Pathway

52. • Acute inflammation may have one of the
four outcomes:
 Complete resolution
 Healing by connective tissue replacement
(fibrosis)
 Progression of the tissue response to chronic
inflammation
 Abcess formation
Outcomes of Acute Inflammation

53. Complete resolution
When?
1) the injury is limited or short-lived
2) there has been little tissue destruction
3) the damaged parenchymal cells can
regenerate
Outcomes of Acute Inflammation

54. Complete resolution
Mechanism:
 Neutralization and removal of chemical
mediators
 Normalization of vascular permeability
 halting of leukocyte emigration
 Clearance of edema (lymphatic drainage) ,
inflammatory cells and necrotic debris
(macrophages).
Outcomes of Acute Inflammation

55. Events in the resolution of
inflammation

56. • Healing by connective tissue replacement
(fibrosis):
• This occurs after substantial tissue destruction
 the inflammatory injury involves tissues that are incapable of
regeneration
 there is abundant fibrin exudation.
 The destroyed tissue is reabsorbed and
eventually replaced by fibrosis.
Outcomes of Acute Inflammation

57. • Progression of the tissue response to
chronic inflammation:
 occurs when the acute inflammatory response
cannot be resolved
 WHY?
Due to: 1. the persistence of the injurious agent
2. some interference with the normal
process of healing
Outcomes of Acute Inflammation

58. End of acute inflammation
More is Lost by Indecision than Wrong Decision