Granulation tissue

Granulation tissue is characterized by proliferation of fibroblasts and new thin-walled, delicate capillaries in a loose extracellular matrix, often with admixed inflammatory cells, mainly macrophages. This tissue progressively invades the site of injury; the amount of granulation tissue that is formed depends on the size of the tissue deficit created by the wound and the intensity of inflammation.

What is repair by scar formation? What are the steps?

If repair cannot be accomplished by regeneration alone, it occurs by replacement of the injured cells with connective tissue, leading to the formation of a scar, or by a combination of regeneration of some residual cells and scar formation.

Steps involved in repair in scar formation:

• Clot formation
• Inflammation
• Angiogenesis and formation of granulation tissue, 
• Migration and proliferation of fibroblasts, 
• Collagen synthesis, 
• Connective tissue remodeling.
  

Repair by regeneration

• Different tissues consist of continuously dividing cells (epithelia, hematopoietic tissues), normally quiescent cells that are capable of proliferation (most parenchymal organs), and nondividing cells (neurons, skeletal and cardiac muscle). The regenerative capacity of a tissue depends on the proliferative
  potential of its constituent cells.
• Cell proliferation is controlled by the cell cycle, and is stimulated by growth factors and interactions of cells with the extracellular matrix.
• Regeneration of the liver is a classic example of repair by regeneration. It is triggered by cytokines and growth factors produced in response to loss of liver mass and inflammation. In different situations, regeneration may occur by proliferation of surviving hepatocytes or repopulation from progenitor cells.

What is Tissue repair? Steps involved in tissue repair.

 Tissue Repair:

Critical to the survival of an organism is the ability to repair the damage caused by toxic insults and inflammation. In fact, the inflammatory response to microbes and injured tissues not only serves to eliminate these dangers but also sets into motion the process of repair.

Repair of damaged tissues occurs by two types of reactions: regeneration by proliferation of residual (uninjured) cells and maturation of tissue stem cells, and the deposition of connective tissue to form a scar.

 1. Regeneration:  Some tissues are able to replace the damaged components and essentially return to a normal state; this process is called regeneration. Regeneration occurs by proliferation of cells that survive the injury and retain the capacity to proliferate, for example, in the rapidly dividing epithelia of the skin and intestines, and in some parenchymal organs, notably the liver.

2. Connective tissue deposition (scar formation):  If the injured tissues are incapable of complete restitution, or if the supporting structures of the tissue are severely damaged, repair occurs by the laying down of connective (fibrous) tissue, a process that may result in formation of a scar.

What are the systemic effects of inflammation?

Inflammation, even if it is localized, is associated with cytokine-induced systemic reactions that are collectively called the acute-phase response.

1. Fever: Cytokines (TNF, IL-1) stimulate production of PGs in hypothalamus.

2. Production of acute-phase proteins: C-reactive protein & others; synthesis stimulated by cytokines (IL-6 & others) acting on liver cells.

3. Leukocytosis: Cytokines (CSFs) stimulate production of leukocytes from precursors in the bone marrow.

4. In some severe infections, septic shock: Fall in blood pressure, disseminated intravascular coagulation, metabolic abnormalities; induced by high levels of TNF and other cytokines.

Examples of diseases with granulomatous inflammation.

• Tuberculosis  Caused by (Mycobacterium tuberculosis)
• Leprosy Caused by (Mycobacterium leprae)
• Syphilis Caused by (Treponema pallidum Gumma)
• Cat-scratch disease Caused by (Gram-negative bacillus)
• Sarcoidosis Unknown etiology 
• Crohn disease (inflammatory bowel disease) Caused by (Immune reaction against undefined gut microbes and, possibly, self antigens).

Mechanism of foreign body granuloma.

Foreign body granulomas are seen in response to relatively inert foreign bodies, in the absence of T cell–mediated immune responses. Typically, foreign body granulomas form around materials such as talc (associated with intravenous drug abuse), sutures, or other fibers that are large enough to preclude phagocytosis by a macrophage but are not immunogenic. Epithelioid cells and giant cells are apposed to the surface of the foreign body. The foreign material can usually be identified in the center of the granuloma, particularly if viewed with polarized light, in which it may appear refractile.

Mechanism of immune granuloma formation

Immune granulomas are caused by a variety of agents that are capable of inducing a persistent T cell–mediated immune response. This type of immune response produces granulomas usually when the inciting agent cannot be readily eliminated, such as a persistent microbe or a self antigen. In such responses, macrophages activate T cells to produce cytokines, such as IL-2, which activates other T cells, perpetuating the response, and IFN-γ, which activates the macrophages.

Tuberculosis is a prototype of immune granuloma.

Define granuloma with example.

Granulomatous inflammation is a form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis. The activated macrophages may develop abundant cytoplasm and begin to resemble epithelial cells, and are called epithelioid cells. Some activated macrophages may fuse, forming multinucleate giant cells. Granuloma formation is a cellular attempt to contain an offending agent that is difficult to eradicate. In this attempt there is often strong activation of T lymphocytes leading to macrophage activation, which can cause injury to normal tissues. 

There are two types of granulomas.

• Immune Granulomas
• Foreign body Granulomas
  

Name different types of granulomatous inflammation.

 Different types of granulomatous inflammation are follows

• Foreign body
• Necrotizing granulomas
• Non-necrotizing granulomas 
• Suppurative granulomas
• Histiocytic response
  

Short Note On "Opsonin"

Opsonins are proteins which coated microbes to enchnace efficiency of phagocytosis.

The major opsonins are 

• Immunoglobulin (Ig)G antibodies, 
• The C3b breakdown product of complement activation, 
• Certain plasma lectins, notably mannose-binding lectin, 

all of which are recognized by specific receptors on leukocytes.

Outline the oxygen dependent mechanism of microbial killing.

Oxygen dependent microbial killing is caused by Reactive oxygen species (ROS)

Reactive Oxygen Species. ROS are produced by the rapid assembly and activation of a multicomponent enzyme, phagocyte oxidase which oxidizes NADPH and, in the process, reduces oxygen to the superoxide anion. In neutrophils, this oxidative reaction is tightly linked to phagocytosis,
and is called the respiratory burst. Phagocyte oxidase is an enzyme complex consisting of at least seven proteins. In resting neutrophils, different components of the enzyme are located in the plasma membrane and the cytoplasm. In response to activating stimuli, the cytosolic protein components
translocate to the phagosomal membrane, where they assemble and form the functional enzyme complex. Thus, the ROS are produced within the phagolysosome, where they can act on ingested particles without damaging the host cell. 

The azurophilic granules of neutrophils contain the enzyme myeloperoxidase (MPO), which, in the presence of a halide such as Cl−, converts H2O2 to hypochlorite, the active ingredient in household bleach. The latter is a potent anti-microbial agent that destroys microbes by halogenation or by oxidation of proteins and lipids. 

The H2O2-MPO-halide system is the most efficient bactericidal system of neutrophils. Nevertheless, inherited deficiency of MPO only causes a modest increase in susceptibility to infection, emphasizing the redundancy of microbicidal mechanisms in leukocytes. H2O2 also is converted to hydroxyl radical (OH•), another powerful destructive agent