Infammation And Repair Pathology Notes

Definitions And General Features

Definition And Causes:

Inflammation is defined as the local response of living mammalian tissues to injury from any agent.

It is a body defence reaction in order to eliminate or limit the spread of injurious agents, followed by removal of the necrosed cells and tissues.

Read And Learn More Infammation And Repair Pathology 

The injurious agents causing inflammation may be as under:

• Infective agents like bacteria, viruses and their toxins, fungi, and parasites.
• Tissue necrosis is caused by various agents such as ischaemia, physical agents (for example, Heat, Cold, Radiation, Mechanical trauma), or chemical agents (for example, (Organic and Inorganic toxins).
• Immunological agents like cell-mediated and antigen-antibody reactions.
• Inert materials such as foreign bodies, dirt, sutures etc.

Thus, it can be inferred from the above that inflammation is distinct from infection— infection is an invasion into the body by harmful microbes and their resultant ill effects, while inflammation is a general protective response by the body to a variety of etiologic agents (infectious or noninfectious).

• Inflammation involves 2 basic processes with some overlapping, viz. early inflammatory response and later followed by repair.
• Though both these processes generally have a protective role against injurious agents, inflammation and healing may cause considerable harm to the body as well.
• For example, Anaphylaxis to bites by insects or reptiles, drugs, toxins, atherosclerosis, chronic rheumatoid arthritis, fibrous bands and adhesions in intestinal obstruction.
• Immunity or immune reaction’ and ‘inflammatory response’ by the host are both interlinked protective mechanisms in the body—while inflammation is the visible response to an immune reaction, activation of the immune response is almost essential before the inflammatory response appears.

Signs Of Inflammation

Although the word inflammation means burning, we now know that burning is only one of the features of inflammation.

• Roman medical writer Celsus in the 1st century A.D. described the famous 4 cardinal signs of inflammation as:

1. Rubor (redness)
2. Tumor (swelling)
3. Calor (heat); and
4. Dolour (pain).

To these, the fifth sign functio laesa (loss of function) was later added by Galen, a pupil of Hippocrates.

Types Of Inflammation

Depending upon the defence capacity of the host and duration of response, inflammation can be classified as acute or chronic:

• There are two types of Inflammation:
  

1. Acute Inflammation
2. Chronic Inflammation

1. Acute inflammation: 

Is of short duration (lasting less than 2 weeks) and represents the early body reaction, resolves quickly and is usually followed by healing.

The main features of acute inflammation are:

• Accumulation of fluid and plasma at the affected site.
• Intravascular activation of platelets, and
• Polymorphonuclear neutrophils as inflammatory cells.

Sometimes, the acute inflammatory response may be quite severe and is termed fulminant acute inflammation.

2. Chronic inflammation:

Is of longer duration and occurs after a delay, either when the causative agent of acute inflammation persists for a long time, or the stimulus is such that it induces chronic inflammation from the beginning.

• A variant form of chronic inflammation, chronic active inflammation, is the type in which there are acute exacerbations of activity during the course of the disease.
• The characteristic feature of chronic inflammation is the presence of chronic inflammatory cells such as lymphocytes, plasma cells and macrophages, granulation tissue formation, and in specific situations granulomatous inflammation.
• In some instances, the term subacute inflammation is used for the state of inflammation between acute and chronic.

Initiation Of Inflammation (Recognition Of Etiologic Agents):

Inflammation is initiated due to the presence of a recognition system of receptors between the etiologic agent (i.e. microbes, necrotic cells) and the participating host cells;

Besides, a few circulating proteins act to trigger inflammation:

• Recognition system of receptors: There are distinct receptors on host cells for microbial agents, leucocytes and for necrotic cells:
  • Receptors for recognition of microbes As discussed in innate immunity pathogen-associated molecular patterns (PAMPs) are present in invading microbes.
  • These PAMPs are recognised by cells other than lymphoid cells participating in innate immunity (epithelial cells, macrophages, dendritic cells) by pattern-recognition receptors located in various components of the participating cells (i.e. on plasma membrane, cytosol, or on endosomes).
  • Among various receptors, most important is toll-like (TLRs) (present on the cytoplasmic membrane and endosomal vesicles); others are NOD-like (NORs) (dispersed in the cytosol) and RIG-like (RIRs) (cytosolic and specific for viruses).
  • Receptors on leucocytes Many leucocytes possess receptors for the Fc component of immunoglobulin antibodies and for complement which recognise microbes coated with antibodies and complement (i.e. opsonised microbes) leading to inflammation and phagocytosis
  • Receptors for recognition of necrotic cells Upon cell death, cytosolic molecules and nuclear DNA are liberated which are recognised by cytosolic receptors (for example, NLRs).
  • Interaction of NLRs with the group of cytosolic and nuclear protein complexes from necrotic cell forms inflammasomes which directly activate caspase-1 (also called interleukin-1β converting enzyme or ICE).
  • Activated caspase-1 secretes proinflammatory cytokines and induces inflammation.
• Circulating proteins:
  • Another set of initiators of inflammation are certain circulating proteins liberated by the activation of the complement system after microbial infection.
  • These include mannose-binding lectins and collectins which act potently against invading organisms and trigger inflammation.

Definitions and General Features:

• Inflammation is the local response of living mammalian tissues to injury from any agent which could be microbial, immunological, physical or chemical agents.
• Cardinal signs of inflammation are redness, swelling, heat, pain and loss of function.
• Inflammation is of 2 types:
  1. Acute when it is due to early response by the body, is of short duration and has infiltration by neutrophils, and chronic when it is for a longer duration, occurs after a delay and is characterised by response by chronic inflammatory cells.
  2. Inflammation is initiated due to the presence of a recognition system of receptors between the etiologic agent (i.e. microbes, necrotic cells) and the participating host cells; besides, certain circulating proteins to act to trigger inflammation.

Acute Inflammatory Response

Acute inflammatory response by the host to any etiologic agent is a continuous process but for discussion.

It can be divided into the following two components:

1. Vascular events
2. Cellular events

Intimately linked to these two processes is the release of mediators of acute inflammation, which is also discussed just afterwards.

1. Vascular Events:

Alteration in the microvasculature (arterioles, capillaries and venules) is the earliest response to tissue injury.

These alterations include:

• Haemodynamic changes, and
• Altered vascular permeability.

Haemodynamic Changes:

• The earliest features of inflammatory response result from changes in the vascular flow and calibre of small blood vessels in the injured tissue. The sequence of these changes is as under:
• Irrespective of the type of cell injury, the immediate vascular response is of transient vasoconstriction of arterioles. With the mild form of injury, the blood flow may be re-established in 3 – 5 seconds while with more severe injury the vasoconstriction may last for about 5 minutes.
• Next follows persistent progressive vasodilatation which involves mainly the arterioles, but to a lesser extent, affects other components of the microcirculation like venules and capillaries.
• This change is obvious within half an hour of injury. Vasodilatation results in increased blood volume in the microvascular bed of the area, which is responsible for redness and warmth at the site of acute inflammation.
• Increased blood volume, in turn, may elevate the local hydrostatic pressure resulting in the transudation of fluid into the extracellular space. This is responsible for swelling at the local site of acute inflammation.
• Slowing or stasis:  Slowing or stasis of microcirculation follows which causes an increased concentration of red cells, and thus, increased blood viscosity.
• Stasis or slowing is followed by leucocytic margination or peripheral orientation of leucocytes (mainly neutrophils) along the vascular endothelium.
• The leucocytes stick to the vascular endothelium briefly, and then move and migrate through the gaps between the endothelial cells into the extravascular space (discussed later under transmigration).
• Triple Response: The features of haemodynamic changes in inflammation are best demonstrated by the Lewis experiment. In this experiment, the skin of the inner aspect of the forearm is stroked firmly with a blunt point and changes are observed.
• The reaction so elicited is known as a triple response or red line response consisting of the following :
  • A red line appears within a few seconds after stroking; this is due to local vasodilatation of capillaries and venules.
  • Flare is the bright reddish appearance or flush surrounding the red line; this results from vasodilatation of the adjacent arterioles.
    Wheal is the swelling or oedema of the surrounding skin; this occurs due to the transudation of fluid into the extravascular space.

These features, thus, elicit the classical signs of inflammation — redness, heat and swelling, to which the fourth feature, pain due to mild trauma to cutaneous nerve endings, has been added.

Altered Vascular Permeability:

• In and around the inflamed tissue, there is an accumulation of oedema fluid in the interstitial compartment which comes from blood plasma by its escape through the endothelial wall of the peripheral vascular bed.
• In the initial stage, the escape of fluid is due to vasodilatation and consequently, increased volume of blood, elevating hydrostatic pressure. This is transudate in nature.
• But subsequently, the characteristic inflammatory oedema, exudate, appears by increased vascular permeability of microcirculation and by the appearance of inflammatory cells (see under vascular events).
• The differences between transudate and exudate, are summarised in
• The appearance of inflammatory oedema due to increased vascular permeability of the microvascular bed is explained on the basis of Starling’s hypothesis.

According to this, normally the fluid balance is maintained by two opposing sets of forces:

1. Forces that cause outward movement of fluid from microcirculation: These are intravascular hydrostatic pressure and colloid osmotic pressure of the interstitial fluid.
2. Forces that cause inward movement of interstitial fluid into circulation: These are intravascular colloid osmotic pressure and hydrostatic pressure of the interstitial fluid.

Whatever little fluid is left in the interstitial compartment is drained away by lymphatics and, thus, no oedema results normally

• However, in inflamed tissues, the endothelial lining of microvasculature becomes more leaky.
• Consequently, intravascular colloid osmotic pressure decreases and osmotic pressure of the interstitial fluid increases resulting in excessive outward flow of fluid into the interstitial compartment which is exudative inflammatory oedema.

Mechanisms Of Vascular Leakiness:

Increased vascular permeability in acute inflammation by which normally non-permeable endothelial layer of microvasculature becomes leaky by following mechanisms which may be acting singly or in combination

• Contraction of endothelial cells:
  • This is the most common mechanism of increased leakiness that affects venules exclusively while capillaries and arterioles remain unaffected.
  • The endothelial cells develop temporary gaps between them due to their contraction resulting in vascular leakiness.
  • It is mediated by the release of histamine, bradykinin and other chemical mediators.
  • The response begins immediately after injury, is usually reversible, and is for a short duration (15-30 minutes).
  • An example of such an immediate transient response is a mild thermal injury of the skin of the forearm.
• Contraction or mild endothelial damage:
  • In some forms of mild injury, there is structural re-organisation of the cytoskeleton of endothelial cells that causes reversible retraction at the intercellular junctions or a mild form of endothelial damage.
  • This change affects venules and capillaries and is mediated by cytokines such as interleukin-1 (IL-1) and tumour necrosis factor (TNF)-α. The onset of response occurs after a delay of 4-6 hours following injury and lasts for several hours to days.
  • A classic example of delayed and prolonged leakage is the appearance of sunburns mediated by ultraviolet radiation or irradiation.
• Direct injury to endothelial cells: 
  • Direct injury to the endothelium causes cell necrosis and the appearance of physical gaps at the sites of detached endothelial cells.
  • The process of thrombosis involving platelets and fibrin is initiated at the site of damaged endothelial cells. The change affects all levels of the microvasculature (venules, capillaries and arterioles).
  • Increased permeability may either appear immediately after injury and last for several hours or days (immediately sustained leakage), or may occur after a delay of 2-12 hours and last for hours or days (delayed prolonged leakage).

Examples of immediate sustained leakage are severe bacterial infections while delayed prolonged leakage may occur following moderate thermal injury and radiation injury.

• Leucocyte-mediated endothelial injury:
  • Adherence of leucocytes to the endothelium at the site of inflammation may result in the activation of leucocytes.
  • The activated leucocytes release proteolytic enzymes and toxic oxygen species which may cause endothelial injury and increased vascular leakiness. This form of increased vascular leakiness affects mostly venules and is a late response.
  • Examples are seen in sites where leucocytes adhere to the vascular endothelium for example, In pulmonary venules and capillaries.
• Transcytosis across the endothelial cytoplasm: 
  • Another mechanism of increased vascular permeability is across the interconnected cytoplasmic channels of endothelial cells i.e. transcellular vesicular-vacuolar organelle transport.
  • This process is stimulated by vascular endothelial growth factor (VEGF).
• Leakiness in neovascularisation:
  • The newly formed capillaries during the process of repair and in tumours are excessively leaky due to intracellular fenestrations; later the endothelial cells mature and develop junctions.

These mechanisms are summarised in a given table

2. Cellular Events:

The cellular phase of acute inflammation includes the recruitment of leucocytes at the site of infection, their activation to recognise the microbe, and eventually phagocytose and clear off the offending agent.

Thus, the cellular phase can be discussed under two headings:

•  Exudation of leucocytes
•  Phagocytosis

Exudation Of Leucocytes:

The escape of leucocytes from the lumen of the microvasculature to the interstitial tissue is the most important feature of inflammatory response. In acute inflammation, polymorphonuclear neutrophils (PMNs) comprise the first line of body defence, followed later by phagocytes (monocytes and macrophages)

 

Mechanisms of increased vascular permeability: