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Flashcards in Inflammation Deck (74):
1

-Haemorrhagic inflammation

Hemorrhagic inflammation indicates severe vascular injury or depletion of coagulation factors 
EXAMPLE: acute pancreatitis

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3. Chemical Agents (irritant and/or corrosive)

Corrosive chemicals (acids, alkalis, oxidizing agents) provoke inflammation through gross tissue damage.

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3 Patterns for Increased Leakage from Vessels

  • 1. An immediate response that is transient, lasts for 30-60 minutes, and is mediated by HISTAMINE acting on endothelium.
  • 2. A delayed response that starts 2-3 hours after injury and lasts for up to 8 hours. This is mediated by factors synthesized by local cells (e.g. BRADYKININ); factors derived from complement; and factors released from dead neutrophils in the exudate.
  • 3. An immediate response that is prolonged for over 24 hours and is seen if there has been DIRECT NECROSIS of endothelium.

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Chemical Mediators (Lysosomal Compounds)

EFFECTS: Increase vascular permeability, increase proteases which may activate complement.

CELLS: Neutrophils (and include cationic proteins)

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-Fibrinous inflammation

When the inflammatory exudate contains plentiful fibrinogen (huge molecule in plasma), this polymerizes into a thick fibrin coating 
EXAMPLE: acute pericarditis

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Chemical Mediators (Lymphokines)

EFFECTS: Chemotaxis or vasoactive

CELLS: Lymphocytes

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Phases of Leukocyte (neutrophil) Journey in Inflammation

1. Margination & Adhesion - move to edge of wall and attach -Pavementing

2. Migration toward chemotaxic stimulus - squeeze through wall and move toward enemy.

3. Phagocytosis & Intracellular degradation
*If tissue damage is extensive, neutrophils from bone marrow will be released.

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Abscess (and removal of it)

Once pus begins to accumulate in a tissue, it becomes surrounded by a 'pyogenic membrane' (walling it off with this membrane to keep it contained) and such a collection is called an abscess (any accumulation of pus in tissue). 

Since bacteria within the abscess cavity are relatively inaccessible to antibodies and to antibiotic drugs surgical incision and drainage is necessary to eliminate the abscess.

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Steps involved in Acute Inflammatory Response (BIG PICTURE)

  • 1. Vasoconstriction (initial transient phase)
  • -Vasodilation - opening of arterioles resulting in active hyperemia.
  • -Slowing of circulation due to increased blood viscosity related to escape of plasma into tissues
  • -Endothelial cells swell and partially retract leaving gaps.
  • -Vessels become leaky and leakage forms exudation (fibrinogen leaks out..?)
  • -Circulating neutrophils adhere to endothelial cells (margination) then actively migrate through basement membrane (emigration), passing into area of tissue damage.
  • -Later, blood monocytes (macrophages) and lymphocytes migrate in similar way.

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Chemical Mediators (Leukotrienes)

EFFECTS: Vasocontriction

CELLS: Neutrophils (mainly)

Synthesized from arachidonic acid, especially in neutrophils, and appear to have vasoactive properties.

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Chemical Mediators of Acute Inflammation: Plasma Factors

The plasma contains four enzymatic cascade systems:
1. Complement system
2. Kinin system
3. Coagulation system
4. Fibrinolytic system

ALL ACTIVATED BY CLOTTING FACTOR XII

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Main Cell Involved in Inflammation

Neutrophils the main cell to mediate effects of inflammation (2-3x bigger than RBCs) but needs to get in to area. 
If need more - access bone marrow.

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Acute Inflammatory Response: 2. Increased Vascular Permeability

  • Small blood vessels lined by endothelial cells. In some tissues, there are areas of endothelial cell thinning = FENESTRATIONS. Allow passage of small materials via diffusion OR ultrafiltration.
  • -High colloid osmotic pressure inside vessel (due to plasma proteins) draws things INTO vessels.
  • -In acute inflammation, capillary hydrostatic pressure increases AND plasma proteins escape into extravascular space resulting in increased colloid osmotic pressure.
  • -MUCH more fluid leaves vessels. Net escape of protein-rich fluid is called exudation.

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Lab Measurements of Acute Inflammation

  • 1. Raised neutrophil count in the peripheral blood (normally 40%)
  • 2. Increased erythrocyte sedimentation rate (ESR).
  • 3. Increase in blood concentration of certain proteins produced by the liver in response to acute inflammation (C-reactive protein)

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Chronic Inflammation characterized by:

In contrast to acute inflammation (which is manifested by vascular changes, edema, and leukocyte infiltration)

A) Infiltration of mononuclear cells (agranulocytes): macrophages, lymphocytes, plasma cells
B) Tissue destruction
C) Fibrosis

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2 Types of Inflammation

2 Types of Inflammation

1. Acute: short-lasting (few days) associated with exudation (escape from blood vessels) of plasma and migration of neutrophils (most abundant WBCs).
EXAMPLES: soar throat, scratch, burn, insect bite

2. Chronic: longer-lasting, associated with presence of lymphocytes and macrophages and the blood vessels and connective tissue proliferation.

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Chronic Inflammation: MPS

Mononuclear Phagocyte System (MPS) consists of monocyte cells that arise from a common precursor in the bone marrow.
-From the blood, monocytes migrate into tissues and transform into macrophages (liver, Kupffer cells; alveolar macrophages)

-Macrophages may be "activated"; a process that results in an increase in cell size and levels of lysosomal enzymes, and greater ability to phagocytose
-Following activation, the macrophages secrete a wide variety of active products (enzymes, plasma proteins, NO - nitric oxide)) that mediate tissue destruction and fibrosis.

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Neutrophil Emigration

Neutrophils and macrophages can insert pseudopodia (part that pulls neutrophil) between endothelial cells, migrate through the gap created between the endothelial cells, and then on through the basal lamina into the vessel wall and enter extravascular space
(ONLY IN VEINS?)

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Phagocytosis

process where cells (like neutrophils and macrophages) ingest solid particles. After adhesion the phagocyte then ingests the attached particle by sending pseudopodia around it forming phagocyte vacuole (also called phagosome) which is bounded by cell membrane.

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Acute Inflammatory Response: 1. Changes in Vessel Caliber

  • Vasoconstriction followed by vasodilation (active hyperemia) lasting 15 min to several hours. 
  • -Can increase bood flow up to 10-fold.
  • -Blood flow slows due to plasma escaping causing increased blood viscosity.
  • -Blood cells begin to flow near vessel wall
  • -"Pavementing" - leukocytes adhere to vascular epithelium.

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5. Functio Leasa (Loss of function)

Movement of an inflamed area is consciously and reflexivly inhibited by pain, while severe swelling may physically immobilize the tissues.

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Chemical Mediators (Histamine)

Best known, 
EFFECTS: Vasodilation, Vascular Permeability
CELLS: mast cells, basophil and eosinophil leukocytes, and platelets. 

Histamine release from those sites (for example, mast cell degranulation) is stimulated by complement components C3a and C5a, and by lysosomal proteins released from neutrophils.

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3. Tumor (Swelling)

Swelling results from edema, the accumulation of fluid in the extra vascular space as part of the fluid exudate.

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Types of Phagocytosis by Neutrophils

Intracellular killing - neutrophils contain 2 kinds of noxious agents:

  • -Oxygen dependent- neutrophils produce hydrogen peroxide which produce noxious agents
  • -Oxygen independent- neutrophis enzyme bacteroferrin binds iron required for bacterial growth

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Margination of Neutrophils

In the normal circulation, cells are confined to the central (axial) stream in blood vessels, and do not flow in the peripheral (plasmatic) zone near to the endothelium. However, loss of intravascular fluid and increase in plasma viscosity with slowing of flow at the site of acute inflammation allow neutrophils to flow in this plasmatic zone. The adhesion of neutrophils to endothelium causes them to aggregate along the vessel walls in a process termed margination.

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Effects of Acute Inflammation

1. Rubor (Redness)
2. Calor (Heat)
3. Tumor (Swelling)
4. Dolor (Pain)
5. Functio Leasa (Loss of function)

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What changes occur to cause inflammatory response?

-Vasoconstriction followed by VASODILATION
-Increased permeability of blood vessels. Allows for:
-Escape of cells from the blood into the tissues.

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2. Constitutional symptoms

Including malaise, anorexia and nausea. Weight loss is common when there is extensive chronic inflammation.

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Process of acute inflammation

1. Occupation of exudate
2. Killing of bacteria
3. Removal of dead tissue

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Outcomes of Acute Inflammation: Organization (favorable outcome circumstances)

Organization of tissues is their replacement by granulation tissue.
During organization:

new capillaries grow into the inert material (inflammatory exudate), macrophages migrate into the zone and fibroblasts proliferate, resulting in fibrosis.

The circumstances favoring this outcome are when:

  • -large amounts of fibrin are formed, which cannot be removed completely (by fibrinolytic enzymes from the plasma or from neutrophil polymorphs)
  • -substantial volumes of tissue become necrotic (or if the dead tissue (e.g. fibrous tissue) is not easily digested)
  • -exudate and debris cannot be removed or discharged completely

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Plasma Cascade Systems: Coagulation System

Converts soluble fibrinogen into fibrin, a major component of the acute inflammatory exudate.

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Systemic Effects of Acute Inflammation

1. Pyrexia
2. Constitutional symptoms
3. Reactive hyperplasia of the reticulo-endothelial system
4. Haematological changes

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1. Microbial Infection

  • One of most common causes.
  • -Viruses (intracellular replication) lead to death of individual cells by intracellular multiplication. 
  • -Bacteria (release specific exotoxins) - chemicals synthesized by them which specifically initiate inflammation 
  • -Parasites and tuberculus inflammation

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Cells Present in Chronic Inflammation (other than macrophages)

  • -Lymphocytes: mobilized in immune reactions and activated by antigen; produce lymphokines that stimulate MPS
  • -Plasma cells: produce antibody
  • -Eosinophils: IgE mediated parasite infections.

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1. Pyrexia

Polymorphs and macrophages produce compounds known as endogenous pyrogens which act on the hypothalamus to set the thermoregulatory mechanisms at a higher temperature to kill off bacteria.

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Clinical Indications of Acute Inflammation

-General weakness (malaise)
-Fever (PYREXIA*)
-Pain
-Rapid pulse rate

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Mediated leakage

Chemical mediators of acute inflammation may cause retraction of endothelial cells, leaving intercellular (leaking) gaps.

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1. Rubor (Redness)

Due to dilation of small blood vessels within the damaged area.
EXAMPLES: Sunburn, or acute conjunctivitis.

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-Catarrhal inflammation

When mucus hypersecretion accompanies acute inflammation of a mucous membrane, the appearance is described as catarrhal
EXAMPLE: common cold

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Plasma Cascade Systems: Kinin System

The kinins are peptides of 9-11 amino acids; 
MOST IMPORTANT: Bradykinin (vascular permeability, mediator of pain)

 

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-Suppurative (purulent) inflammation

The terms 'suppurative' and 'purulent' denote the production of pus, which consists of dying and degenerate neutrophils, infecting organisms and liquefied tissues. The pus may become walled-off by granulation tissue or fibrous tissue to produce an abscess.
EXAMPLE: a localized collection of pus in a tissue

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Outcomes of Acute Inflammation: Supporation

Suppuration is the formation of pus, a mixture of living, dying and dead neutrophils and bacteria and cellular debris. 

The causative stimulus must be fairly persistent and is virtually always an infectious agent, usually PYOGENIC BACTERIA.

 

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Plasma Cascade Systems: Fibrinolytic System

Plasmin is responsible for the lysis of fibrin into fibrin degradation products, which may have local effects on vascular permeability.

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Plasma Cascade Systems: Complement System

Cascade system of enzymatic proteins.
Products of complement activation most important in acute inflammation include:
C1-9 -C5a, 3a: histamine release - chemotactic for neutrophils; increases vascular permeability; releases of histamine
C3a: similar properties to those of C5a, but less active
C567: chemotactic for neutrophils
C56789: cytolytic activity
C4b, 2a, 3b: opsonization of bacteria (facilitates phagocytosis by macrophages).

Opsonization - facilitates phagocytosis by molecule inding to surface of bacterium.

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4. Haematological changes

  • -Increased erythrocyte sedimentation rate (an increased erythrocyte sedimentation rate is a non-specific finding in many types of inflammation).
  • -Leukocytosis (neutrophilia occurs in pyogenic infections and tissue destruction; eosinophilia in allergia & parasitic infection).
  • -Lymphocytosis (in chronic infection, many viral infections).
  • -Monocytosis (occurs in infectious mononucleosis and certain bacterial infections).

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Role of the Lymphatics in Inflammation

Terminal lymphatics are blind-ended, endothelium-lined tubes present in most tissues in similar numbers to capillaries. 

The terminal lymphatics drain into collecting lymphatics which have valves and so propel lymph passively, aided by contraction of neighboring muscles, to the lymph nodes. 

In acute inflammation, the lymphatic channels become dilated as they drain away the edema fluid of the inflammatory exudate. This drainage tends to limit the extent of edema in the tissues.

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Non-mediated leakage

Toxins and physical agents may cause necrosis of vascular endothelium, leading to abnormal leakage.

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When does chronic inflammation occur?

1. follows acute inflammation when inflammatory response is unable to eliminate injurious agents

2. Chronic almost from the onset often when the injurious agents are less toxic then those that lead to acute inflammation (e.g. persistent infections, autoimmune diseases)

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Acute Inflammatory Response: 3. Factors of Increased Vascular Permeability

2 mechanisms:
1. Non-mediated leakage
2. Mediated leakage

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Colloid Osmotic Pressure

Pressure in blood created by particles in it. Force that holds water within
Colloid = protein. When start losing particles, water will follow. (albumin most important)

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Main Neutrophil Chemotactic Factors

-bacterial components
-complement system components (C5a).
-Arachidonic acid derivatives (leukotriene B4)

These factors bind to receptors on the surface of neutrophils and activate secondary messenger systems, stimulating increased cytosolic calcium, which causes them to move toward site of injury.

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5. Tissue necrosis

Death of tissues from lack of oxygen or nutrients resulting from inadequate blood flow (infarction).

The edge of a recent infarct often shows an acute inflammatory response.

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Chemical Mediators of Acute Inflammation (List 5)

  • Histamine
  • Lysosomal compounds
  • Prostaglandins
  • Leukotrienes
  • Lymphokines

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Possible Outcomes of Acute Inflammation

1. Resolution
2. Suppuration
3. Organization
4. Chronic Inflammation

 

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2. Physical Agents

-Physical trauma
-Ultraviolet light
-Ionizing radiation
-Thermo-related - excessive heat or cold

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Chemical Mediators of Acute Inflammation

Chemical substances are released from injured tissues, spreading outwards into uninjured areas. 
EFFECTS:
-Vasodilation
-emigration of neutrophils
-chemotaxis
- increased vascular permeability

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Outcomes of Acute Inflammation: Chronic Inflammation

If the agent causing acute inflammation is not removed, the acute inflammation may progress to the chronic stage. 

In addition to organization of the tissue just described, the character of the cellular exudate changes, with lymphocytes - plasma cells and macrophages - neutrophils.

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The sequelae of acute inflammation depends on:

  • Nature of the injurious agent
  • Type of tissue involved
  • Amount of tissue destruction

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Outcomes of Acute Inflammation: Resolution (conditions which favor it)

Complete restoration of the tissues to normal.

The conditions which favor resolution are:

  • -minimal cell death and tissue damage
  • -occurrence in an organ or tissue which has regenerative capacity (e.g. the liver) rather than in one which cannot regenerate (e.g. the CNS/heart)
  • -rapid destruction of the causal agents (e.g. phagocytosis of bacteria)
  • -rapid removal of debris by vascular drainage

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4. Dolor (Pain)

Results partly from the stretching and distortion of tissues due to inflammatory edema and, in particular, from pus under pressure in an abscess cavity. 

Some of the chemical mediators of acute inflammation, including bradykinin, the prostaglandins and serotonin, are known to induce pain.

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Types of Inflammation by appearance (Macroscopic appearance)

-Serous inflammation
-Catarrhal inflammation
-Fibrinous inflammation
-Haemorrhagic inflammation
-Suppurative (purulent) inflammation

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Chemical Mediators (Prostaglandins)

EFFECTS: Platelet aggregation, vascular permeability

CELLS: Group of long-chain fatty acids derived from arachidonic acid and synthesized by many cell types.

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CI: Granulomatous Inflammation

Special kind of chronic inflammation which occurs in the presence of indigestible material. 

  • -Granuloma is an abnormal structure built from at least two activated macrophages adhering to one another forming giant multinuclear cells (Langhans giant cells). This occurs because substance is too big to eliminate or indigestible.

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4. Hypersensitivity

Altered state of immunological responsiveness causes an inappropriate/excessive immune reaction which damages the tissues.

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3. Reactive hyperplasia of the reticulo-endothelial system:

Local or systemic lymph node enlargement

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Inflammation

Protective response of living tissue to damage, whose ultimate goal is to rid the cause of cell injury (eg microbes and toxins) and the results of such injury (eg necrotic cells)

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Formation of Cellular Exudate

1. Activation of endothelium - need to be activated to allow adhesions of neutrophils

2. Activation of neutrophils - activate to enhance capacity for phagocytosis, bacterial killing and generation of inflammatory indicators.

3. Neutrophil movement - Develop ability to move (actively) toward tissue damage.

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Causes of Acute Inflammation

1. Microbial Infection
2. Physical Agents
3. Chemical Agents (irritant and/or corrosive)
4. Hypersensitivity (Immunological issue)
5. Tissue necrosis

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-Serous inflammation

An abundant protein-rich fluid exudate with a relatively low cellular content. 
EXAMPLES: inflammation of the serous cavities, such as peritonitis, and inflammation of a synovial joint, acute synovitis.

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2. Calor (Heat)

Increase in temperature due to increased blood flow (hyperemia) through the region, resulting in vascular dilation and the delivery of warm blood to the area.

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Later Stages of Acute Inflammation: Chemotaxis of Neutrophils

Movement of neutrophils mediated by chemotactic factors - substance that diffuses from tissue damage.

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Diapedesis

Blood cells escaping capillary via passive process and depends on hydrostatic pressure forcing the cells out.