Inflammation and Healing in Pathology

If you’re a medical student and want to study Inflammation and Healing in Pathology then I am going to cover this topic in this article. Inflammation is the local response of living mammalian tissues to injury by any agent, which can be microbial, immunological, physical, or chemical agents.

Cardinal signs of inflammation are redness, swelling, heat, pain and loss of function.

Definition:

Inflammation is defined as the local response of living mammalian tissues to injury from some agent. It is a defensive response by the body to eliminate or limit the spread of the harmful agent, followed by the removal of the necrotic cells and tissues.

Causes:

The harmful agents that cause inflammation can be as follows:

1. Infectious agents such as bacteria, viruses, and their toxins, fungi, parasites.

2. Immunological agents such as cell-mediated and antigen-antibody reactions.

3. Physical influences such as heat, cold, radiation, mechanical trauma.

4. Chemical agents such as organic and inorganic poisons. 5. Inert materials such as foreign bodies.

Thus, inflammation is different from infection – inflammation is a protective response by the body to a variety of etiological agents (infectious or non-infectious), while the infection is an invasion of the body by harmful microbes and their resulting negative effects from toxins. Inflammation involves 2 basic processes with some overlap, viz. early inflammatory response and later followed by healing. Although both of these processes generally act as protection against harmful agents, inflammation and healing can also cause significant damage to the body, e.g. Anaphylaxis for insect or reptile bites, drugs, toxins, atherosclerosis, chronic rheumatoid arthritis, fibrous ligaments, and adhesions in intestinal obstruction.

As mentioned earlier, the host’s “immunity or immune response” and “inflammatory response” are both interrelated protective mechanisms in the body – inflammation is the visible response to an immune response, and activation of the immune response is almost essential before an inflammatory response occurs.

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Signs Of Inflammation and Healing

The Roman writer Celsus in the 1st century AD named the famous 4 cardinal signs of inflammation as follows:

i) rubor (redness)
ii) tumor (swelling)
iii) calor (heat)
iv) dolor (pain)

To these, the fifth sign function laesa (loss of function) was later added by Virchow. The word inflammation means burning. This nomenclature had its origin in old times but now we know that burning is only one of the features of inflammation.

Types Of Inflammation

Inflammation is of 2 types: acute when due to early response by the body and is of short duration, and chronic when it is for longer duration and occurs after delay and is characterized by a response by chronic inflammatory cells.

A. Acute inflammation:

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 as fulminant acute inflammation.

B. Chronic inflammation:

Chronic inflammation is of a longer duration and occurs with a delay, either after the causative agent of the acute inflammation persists for a long time or the stimulus is such that it induces chronic inflammation from the beginning. One variant, chronic active inflammation, is the form of chronic inflammation in which there is an acute increase in activity over 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, the formation of granulation tissue and, in certain situations, as granulomatous inflammation. In some cases, the term subacute inflammation is used for the inflammatory state between acute and chronic.

HEALING

Healing is the body’s response to an injury to restore normal structure and function. It includes 2 processes:

  1. Regeneration: when healing takes place by the proliferation of parenchymal cells and usually results in complete restoration of the original tissues.
  2. Repair: when healing takes place by the proliferation of connective tissue resulting in fibrosis and scarring. At times, both these processes take place simultaneously.

Regeneration:

Some parenchymal cells are short-lived while others have a longer lifespan. In order to maintain the proper structure of tissues, these cells are under the constant regulatory control of their cell cycle. These include growth factors such as: epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, endothelial growth factor, transforming growth factor-b.

Parenchymal cells in relation to cell cycle
Parenchymal cells in relation to cell cycle (G0–Resting phase; G1, G2–Gaps; S–Synthesis phase; M–Mitosis phase)

Parenchymal cells in relation to the cell cycle (G0 resting phase; G1, G2 gaps; S synthesis phase; M mitosis phase). The inner circle shown with a green line represents the cell cycle for labile cells; Circle with yellow-orange line shows the cell cycle for stable cells; and the circle shown with red line represents the cell cycle for permanent cells. Compare them with traffic lights – green stands for “go” and applies here to unstable cells that are dividing; yellow-orange signal for “ready to go” applies here to stable cells that can be stimulated to enter the cell cycle; and the red signal for “stop” means permanent cells that are not dividing.

Cell cycle is defined as the period between two successive cell divisions and is divided into 4 unequal phases.

  • M (mitosis) phase: Phase of mitosis.
  • G1 (gap 1) phase: The daughter cell enters G1 phase after mitosis.
  • S (synthesis) phase: During this phase, the synthesis of nuclear DNA takes place.
  • G2 (gap 2) phase: After completion of nuclear DNA duplication, the cell enters G2 phase.
  • G0 (gap 0) phase: This is the quiescent or resting phase of the cell after an M phase.
  • The period between the mitosis is called interphase

Not all cells in the body divide at the same rate. Some mature cells do not divide at all while others cycle through cells every 16-24 hours. The main difference between slowly dividing and rapidly dividing cells is the duration of the G1 phase. Depending on their ability to divide, the body cells can be divided into 3 groups: labile cells, stable cells and permanent cells. Now we further discuss and continue Inflammation and Healing in Pathology.

1. Labile cells:

These cells continue to multiply throughout life under normal physiological conditions. These include surface epithelial cells of the epidermis, digestive tract, airways, urinary tract, vagina, cervix, the endometrium of the uterus, hematopoietic cells of the bone marrow, and cells of the lymph nodes and spleen.

2. Stable cells:

These cells decline or lose their ability to reproduce after adolescence, but retain the ability to reproduce in response to stimuli throughout adult life. These include: parenchymal cells from organs such as the liver, pancreas, kidneys, adrenal glands, and thyroid glands; mesenchymal cells such as smooth muscle cells, fibroblasts, vascular endothelium, bone and cartilage cells.

3. Permanent cells:

These cells lose their ability to reproduce around the time of birth. These include: neurons of the nervous system, skeletal muscle and heart muscle cells.

Repair

Repair is the replacement of injured tissue by fibrous tissue. Two processes are involved in repair:

  • Granulation tissue formation
  • Contraction of wounds

The repair response occurs through the involvement of mesenchymal cells (consisting of connective tissue stem cells, fibrocytes and histiocytes), endothelial cells, macrophages, blood platelets and the parenchymal cells of the injured organ.

Active granulation tissue has inflammatory cell infiltrate, newly formed blood vessels and young fibrous tissue in loose matrix.
Active granulation tissue has inflammatory cell infiltrate, newly formed blood vessels and young fibrous tissue in loose matrix.

Granulation Tissue Formation:

The term granulation tissue derives its name from the slightly grainy and pink appearance of the tissue. Each granulate corresponds histologically to the proliferation of new small blood vessels, which are slightly raised on the surface by a thin cover with fibroblasts and young collagen.

The following 3 phases are observed in the formation of granulation tissue (above image)

1. PHASE OF INFLAMMATION Following trauma, blood clots at the site of injury. There is acute inflammatory response with exudation of plasma, neutrophils and some monocytes within 24 hours.

2. PHASE OF CLEARANCE Combination of proteolytic enzymes liberated from neutrophils, autolytic enzymes from dead tissues cells, and phagocytic activity of macrophages clear off the necrotic tissue, debris and red blood cells.

3. PHASE OF INGROWTH OF GRANULATION TISSUE This phase consists of 2 main processes: angiogenesis or neovascularization, and fibrogenesis.

i) Angiogenesis (neovascularization) The formation of new blood vessels at the injury site occurs through the proliferation of endothelial cells from the edges of severed blood vessels. Initially, the proliferated endothelial cells are solid buds, but within a few hours they develop a lumen and begin to transport blood. The newly formed blood vessels are leaky, which is responsible for the edematous appearance of new granulation tissue. Soon these blood vessels differentiate into muscle arterioles, thin-walled venules and real capillaries. The process of angiogenesis is stimulated by proteolytic destruction of the basement membrane. Angiogenesis takes place under the influence of the following factors: a) Vascular Endothelial Growth Factor (VEGF), which is formed by mesenchymal cells, while its receptors are only present in endothelial cells. b) Platelet-derived growth factor (PDGF), transforming growth factor-b (TGF-b), basic fibroblast growth factor (bFGF) and surface integrins are all associated with cell proliferation.

ii) Fibrogenesis The newly formed blood vessels are in an amorphous basic substance or matrix. The new fibroblasts have characteristics that lie between those of fibroblasts and smooth muscle cells (myofibroblasts). Collagen fibrils begin to appear around day 6. The myofibroblasts have surface receptors for fibronectin molecules that form bridges between collagen fibrils. As maturation progresses, more and more collagen is formed, while the number of active fibroblasts and new blood vessels decrease. This leads to the formation of an inactive looking scar; This process is known as scarring.

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