Pathology Course Chapter 2

SECTION 2.1 ACUTE INFLAMMATION

Topics
y Introduction  Definition of Inflammation  Acute vs. Chronic  Cardinal Signs of Acute Inflammation y Causes of Acute Inflammation y The Events of Acute Inflammation  Vascular Changes  Cellular Changes y Morphology of Acute Inflammation y Outcome of Acute Inflammation

Introduction
DEFINITION OF INFLAMMATION ACUTE VS. CHRONIC CARDINAL SIGNS OF ACUTE INFLAMMATION

What is inflammation?

Inflammation is a response by the body to injury, intended to remove the injurious agent, remove dead cells, and repair the area. It is indicated by the suffix -itis (e.g. pericarditis).

Acute vs. Chronic

Acute Inflammation

Chronic Inflammation

Few hours

More than that... up to years!!!

up to few days...

The basic difference between the two is that in acute inflammation the removal of injurious agent and repair can be done fast and easy, but in chronic inflammation they cant.

Cardinal Signs of Acute Inflammation

Rubor Calor Tumor Dolor Functio laesa

Redness of the area because of vasodilation Warmth of the area because of vasodilation Swelling of the area because of edema Pain due to stimulatnion of nerve endings Loss of function in the area because of edema and pain

Causes of Acute Inflammation

INFECTIONS TISSUE NECROSIS FOREIGN BODIES IMMUNE REACTIONS

Infections

Immune cells recognize microbes by many receptors, such as Toll-like receptors and many cytoplasmic receptors. This recognition triggers signal transduction pathways, leading to release of mediators, and initiation of inflammation.

Tissue Necrosis

This is a sample from the heart, showing extensive inflammation after an infarction. Tissue necrosis from any cause will induce inflammation. This is due to many materials released from necrotic cells (e.g. uric acid, adenosine, etc.) that induce inflammation.

Tissue Necrosis

This is an example of inflammation due to tissue necrosis from a frostbite [Frostbite occurs when there is extreme cold, causing constriction of peripheral blood vessels, leading to ischemia and necrosis.]

Foreign Bodies

Foreign bodies can cause inflammation because they are foreign! They may even do it by causing traumatic necrosis, or by carrying microbes.

Immune Reactions

Pencillin rash (left) and hay fever (right) are cases of immune-related inflammation. The immune system will attack anything that is foreign. Sometimes even things that are not foreign! Inflammation in this case is due to cytokines released by activated T cells.

The Events of Acute Inflammation

VASCULAR CHANGES CELLULAR CHANGES LEUKOCYTE-INDUCED DAMAGE STOPPING INFLAMMATION

Vascular Changes

Stasis Increased Permeability

Vasodilatation

Vasoconstriction

Vascular Changes

The main mediators for vasodilatation are histamine and nitric oxide (released from nearby cells). This causes fluid loss, hence stasis of the blood.

Increased Vascular Permeability

Endothelial cell contraction
Mediated by histamine and other mediators released at the site Immediate and short-lived (immediate transient response)

Endothelial injury
Leukocytemediated damage

If the injurious agent also damaged blood vessels Can either be immediate and prolonged (immediate sustained response) or delayed and prolonged (delayed prolonged response)

When the leukocytes arrive later on, they can injure the vessels by their enzymes.

Increased Vascular Permeability

Edema

Transudate is accumulation of fluid with little protein content and low specific gravity outside blood vessels. Exudate has higher protein content and specific gravity.

Edema
Increased hydrostatic pressure or decreased oncotic pressure Low protein content, hence low specific gravity Seen in inflammation, heart failure, nephrotic syndrome, etc.

Transudate

Exudate

Vasodilation and increased permeability High protein content, hence high specific gravity Seen only in inflammation

Lymphatic Involvement

Lymphatic drainage increases during inflammation. If the offending agent is also carried away, inflammation can even involve the lymphatic vessels (lymphangitis) or even the lymph nodes (lymphadenitis). Red streaks on the arm emanating from a wound indicate lymphangitis.

Cellular Changes
y The aim of bringing neutrophils

to the area is to:

   

kill infectious agents if present remove any foreign material present remove necrotic tissue produce growth factors that aid in repair

y The price is:  normal tissue may be damaged  inflammation may get prolonged

Cellular Changes

Margination and Rolling

Adhesion

Transmigration

Chemotaxis

Margination
y Normal blood flow has:  central axial flow of RBCs  more peripheral flow of neutrophils y In inflammation:  stasis of blood flow (because of fluid transudation) will allow more peripheral movement of leukocytes and more contact with endothelium  this is called margination

Rolling
y As leukocytes marginate, they start binding to and

detaching from the endothelium by a set of complementary adhesion molecules called selectins
y There are three types of selectins:  L-selectin: on leukocytes  E-selectin: on endothelium  P-selectin: on endothelium (and platelets)

Selectins
y Normally the selectins are not active; they get activated

during inflammation
y During inflammation the offending agent and necrotic

cell debris will come into contact with macrophages, mast cells, and endothelial cells
y These cells will secrete cytokines like TNF, IL-1, and

chemokines
y These cytokines activate the selectins

Selectins
y TNF and IL-1 will activate E-selectin and the ligand

for L-selectin on the nearby venular endothelium

Selectins
y P-selectins are normally sequestered in Weibel-

Palade bodies in endothelial cells y Histamine and thrombin stimulate their redistribution to the cell surface

Adhesion
y The tumbling leukocytes can now bind more firmly

to the endothelium using their integrin receptors y Expression of integrin ligands on the endothelium is stimulated by TNF and IL-1

Adhesion
y The integrin receptors on the leukocytes are

normally low-affinity y Chemokines that have entered the endothelial cells during inflammation bind the leukocytes and change their integrins to high-affinity state

Transmigration
y After firm adehsion, chemokines will stimulate the

migration of the adhered leukocytes between the endothelial cells (diapedesis) to the outside
y The movement is mediated by binding to molecules

on the endothelial cells, such as PECAM-1

y On reaching the basement membrane of the

endothelial cells, the leukocytes will secrete collagenases to break them down and move on

Chemotaxis
y After leaving the blood vessel, the leukocytes

continue moving toward the injury site under the effect of many substances
y During this part of the journey, the leukocytes

remain localized to the injured tissue by using their integrins and CD44 molecules to bind to matrix proteins like fibronectin

Cellular Changes

Leukocyte Adhesion Deficiency

y Two types:  LAD-1 due to defect in integrins  LAD-2 due to absence of ligand for E-selectin and P-selectin y Neutrophils cannot exit the

vessels during inflammation



There will be high levels of neutrophils in blood during infection

y There will be recurrent bacterial

infections and absence of pus

Chemotaxis
y How chemotaxis occurs:  Chemoattractans bind to receptors on the leukocyte  This initiates a signal transduction pathway  The result is rearranging the cell's contractile elements to increase polymerized actin at the leading end and myosin at the back  Leukocyte begins moving by trailing tail extending filopodia  Direction of movement depends on chemoattractant gradient

filopodium

Chemotaxis

y Chemoattractants for leukocytes include: 1. Bacterial products 2. C5a complement product 3. Chemokines 4. Leukotriene B4

Type of Recruited Cell

y Neutrophils predominate in 6 to 24 hours because
   

they are more numerous in blood respond better to chemokines bind more strongly to selectins are short-lived and die soon

y Macrophages predominate at 24 to 48 hours because



they are more long-lived

y Exceptions!
  

Pseudomonas infections call neutrophils for days Viral infections call lymphocytes Eosinophils predominate in hypersensitivity reactions

Type of Recruited Cell

Type of Recruited Cell

Mainly neutrophils (early phase)

Mainly macrophages (late phase)

TNF Inhibitors
y TNF is a major cytokine involved

in recruiting leukocytes
y TNF inhibitors can reduce

inflammation in inflammatory diseases like rheumatoid arthritis

y Side effect would obviously include

increased risk for infections

Activation of Leukocyte

Phagocytosis
y After the leukocyte has arrived at the injury site and

comes into contact with the offending agent, it starts phagocytosing it in three steps:
  

Recognition Engulfment Destruction

Recognition and Engulfment

y Recognition of a microbe or a foreign antigen is done

through receptors like:



Mannose receptors (which only recognize bacterial sugars and not mammalian sugars) Scavenger receptors (binding microbes, as well as another role in binding oxidized LDL in atherosclerosis) Opsonin receptors (receptors for opsonins like IgG, C3b, and mannan-binding lectin)

y Engulfment of the offending agent into a phagosome

is due to a rearrangement of actin filaments

Recognition and Engulfment

H2O2-MPO-Halide System
y The most potent killing system in neutrophils is the

H2O2-MPO-halide system y The enzyme phagocyte oxidase (NADPH oxidase) generates free radicals in the phagosome to kill the agent y Parts of the enzyme are normally scattered in the cytoplasm and cell membrane; they are assembled at the phagosome membrane upon activation y The enzyme oxidizes NADPH to reduce oxygen into superoxide

H2O2-MPO-Halide System
y Superoxide is spontaneously converted into H2O2 y Meanwhile, a lysosome fuses with the phagosome

so that MPO (myeloperoxiase) now can be released from the lysosome into the phagosome y MPO uses chloride to convert H2O2 into hypochlorite (OCl.), which is also found in bleach y Hypochlorite is a powerful destructive agent

Killing the Offending Agent

Other Weapons
y The leukocytes also use other weapons to fight

microbes:
      

Elastase Defensins Cathelcidins Lysozyme (for bacterial cell walls) Lactoferrin Major basic protein (for parasites) Bactericidal/permeability increasing protein (for gramnegative bacteria)

Activating Tissue Repair and Stopping Inflammation

Macrophages can enhance inflammation, or stop it and induce tissue repair, depending on the stimulus they receive.

Tissue Damage from Leukocytes

y Activation of leukocytes during inflammation can

damage self tissues in a number of settings:

  

Normal inflammatory response to a harmful foreign agent Autoimmune diseases where the target is self tissue Excessive inflammatory response to a harmless foreign agent

y Self tissue damage occurs from enzymes released

from the leukocyte due to:



 

Inability to phagocytose the target agent (frustrated phagocytosis) Formation of phagolysosome before closure of phagosome Damage to phagolysosome membrane from urate crystals

Chdiak-Higashi Syndrome
y Defective fusion of phagosome and

lysosome
y This delays microbial killing and

causes susceptibility to infections

y Giant granules seen in

macrophages from aberrant phagolysosome formation

y Patients also have albinism, nerve

defects, and bleeding

Chronic Granulomatous Disease

y Defect in phagocyte oxidase

(different variants depending on the affected enzyme subunit)

y Susceptibility to recurrent

bacterial infections
y As neutrophils cannot control the

situation, macrophages come and form granulomas

Granuloma

Acquired Leukocyte Deficiency

y This is the most common scenario

of leukocyte defect, and is due to bone marrow suppression

y Marrow suppression will

decrease the production of leukocytes

y It could be from drugs, cancer

radiotherapy or chemotherapy, or tumors in the marrow (e.g. leukemia, metastasis, etc.)

Stopping Inflammation
y Inflammation slows down and stops due to:  on-demand release (from a stimulus) and very short half-life of inflammatory mediators  short half-life of neutrophils  production of lipoxins, TGF-B, IL-10, resolvins, and protectins later in the inflammatory response  cholinergic neural inhibition of TNF production in macrophages

Morphology of Acute Inflammation

SEROUS INFLAMMATION FIBRINOUS INFLAMMATION PURULENT INFLAMMATION ULCERS

Morphology of Acute Inflammation

y In general, acute inflammation is manifested by

congested blood vessels, stasis, edema, and leukocytic infiltrate in tissues

Morphology of Acute Inflammation

y Special patterns of morphology can be recognized

depending on the site and cause involved:

   

Serous inflammation Fibrinous inflammation Purulent inflammation Ulcers

Serous Inflammation
y This

type of inflammation shows accumulation of serous fluid, either derived from plasma or from mesothelial secretions (when in one of the three body cavities, called an effusion). Examples are viral and burn blisters.

Serous Inflammation

serous fluid separating epidermis from dermis

Fibrinous Inflammation
y This occurs when there is

exudation of large amount of fibrinogen (due to large vascular leak) or when there is local procoagulant stimuli from cancer cells y This usually occurs in meninges, pericardium, and pleura y Persistence of fibrin can stimulate fibroblast and blood vessel ingrowth, leading to organization

Fibrinous Inflammation

Fibrinous pericarditis can result from 6 general causes, including acute myocardial infarction, infections, cardiac surgery, and others

Purulent Inflammation
y Characterized by formation

of pus, which is a collection of dead neutrophils, liquefactive necrosis, and edema fluid y Caused by pyogenic (pusforming) bacteria like Staphylococcus species y If the pus is buried deep in a tissue, organ, or confined space, it is called abscess

Purulent Inflammation - Abscess

Outermost zone of vascular dilation, and parenchymal and fibroblastic proliferation

Outer zone of preserved neutrophils Core of necrotic tissue cells and leukocytes

Ulcers
y Ulcer is a defect in the surface of a tissue or organ

due to the sloughing of necrotic inflamed tissue y Seen in the mucosa of GIT (e.g. gastric ulcer, duodenal ulcer, etc) and GUT

uod nal ulcer

Ulcers
y Seen in the skin and subcutaneous tissue of

lower extremities in diabetics (because of extensive ischemic necrosis)

Outcome of Acute Inflammation

Outcome of Acute Inflammation

y Acute inflammation can end in:  Resolution: the injurious stimulus is removed, cellular debris is removed, parenchyma regenerates, and function is regained  Fibrosis (organization): if there is substantial damage, or parenchyma cannot regenerate, or there was large amount of exudate, there will be collagen deposition in the area and loss of function  Progression to Chronic Inflammation: this occurs when the injurious stimulus cannot be removed easily. Examples include pneumonia leading to chronic lung abscess, tuberculosis, etc.

How resolution occurs