HEALING

Definition. Replacement of damages tissue by healthy tissue. It is an attempt to restore the tissue to structural and functional normalcy.

Healing may be of 2 types

A. Regeneration.

B. Repair by granulation tissue.

A. Regeneration

Where the replacement is by proliferation of parenchymatous cells of type destroyed. This depends upon:

(1) Regenerative capacity of cells. Cells may be :

(a) Labile cells which are constantly proliferating to replace cells continuously shed off or destroyed

Epithelial cells of skin and lining surfaces.

Lymphoid and haemopoietic tissue.

(b) Stable cell. Cells mostly in resting-phase, but capable of dividing when necessary e.g.

• Liver and other parenchymatous and glandular cells.
• Connective tissue cells.
• Muscle cells have a limited capacity to divide.

(c) Permanent cell. These cells, once differentiated are not capable. of  dividing e.g.-nerve

(2) The extent of tissue loss. If  there is extensive destruction including disruption of the framework, complete.regeneration is not possible. even with labile an stable cell

B. Repair by granulation tissue

Granulation tissue is formed by proliferation of surrounding connective tissue elements. which migrate into the site to be repaired.

Granulation tissue formation  seen in :

• Wound healing.
• Organisation of exudates.
• Thrombi.
• Infarcts.
• Haematomas.

The process of repair can be best studied in clean incised wounds, where there is .no or minimal tjssue loss or the_edges or the  edges of the wound are approximated closely as in a surgical wound. This is called Primary union (healing by first intention).

1. The blood in the incised area clots and the fibrin binds the edges together.

2. During the first 24 hours, an acute  inflammation sets in to .bring protein and phagocyte rich exudates to the site.

3. The superficial part of the clot get dry and dehydrated{scab). The surface epithelium proliferates just beyond the cut edges and the cells migrate-deep to dry scab. Epithelialisation is usually complete by 24- 48 hours.

4 Granulation tissue, with actively growing fibroblasts and capillary buds invades the clot (stage of vascularisation). These fibroblasts 'posses contractile myofibrils & hence are termed as myofibroblasts'.

5. Simultaneously, demolition of the debris and clot components takes place.

6 The granulation tissue initially lays down a mucopolysacharide rich ground substance

7.Reticulin and later collagen fibrils are formed by the fibroblasts (with 5 days)

8 with progressive maturation of collagen, some of the capiliary buds develop into arterioles and venules and majority of them are obliterated (stage of devascularisation).

9. With time (weeks to months) the tensile strength of the scar increases and it shrinks.

Secondary union (excised wound-healing by secondary intention).

1. Coagulum forms and fills the gap.

2. Inflammatory reaction is seen as in primary union but is more intense, as a lot more debris has to be removed. .

3. Epithelial proliferation starts covering the surface from the periphery by proliferation beyond the edges and migration under scab.

4.Debridement starts and simultaneously granulation tissue grows into the coagulum from the sides and base of the wound. This is much more exuberant than in primary union. The surface now looks red and granular.

5. Wound contraction. This is early contraction (starts after 3 days and is complete in 2 weeks) and  must be differentiated from contraction after scar formation Wounds can contract by up to 80% of original size of that the gap to be filled is much reduced, resulting in faster healing with a smaller scar.

Wound contraction is probably caused by:

• Dehydration
• Collagen contraction.
• Granulation tissue contraction .(myofibroblasts).

The exact mechanism is not known.

6. Laying down of collagen.

7 Maturation to form a scar which later shrinks and devascularises.

Factors affecting wound healing

Wound healing is delayed by :

A. Local  factors

1. Poor blood supply.

2. Adhesion to bony surfaces (e.g. over the tibia).

3. Persistent injurious agents (infective or particulate) results in chronicity of  inflammation and ineffective healing. .

4. Constant movement (especially in fracture healing).

5. ionizing radiation (in contrast, ultraviolet rays hasten healing).

6. Neoplasia.

B. General factors

I. Nutritional deficiency, especially of.

(i) Protein

(ii) Ascorbic acid (Vitamin C).

(iii) Zinc

2. Corticoids adversely affect wound contraction and granulation tissue formation

(anabolic steroids have a favorable effect).

3. Low temperature.

4. Defects (qualitative or quantitative) in polymorphs and macrophages

.Complication of wound healing

1. Wound dehiscence

2.  Infection

3. Epidermal inclusion (implantation) cysts.

4. Keloid formation

5. Cicatrisation resulting in contract Ires and obstruction(in hollow viscera).

6. Calcification and ossification.

7. Weak scar which could be a site for incisional hernia

8. Painful scar if it involves a nerve twig.

9. Rarely neoplasia (especially in burn scars).

The Specific Immune Response

Definition

The immune response comprises all the phenomenon resulting from specific interaction of cells of the immune-system with antigen. As a consequence of this interaction cells  appear that mediate cellular immune response as well cells that synthesis and secrete immunoglobulins

Hence the immune response has 2 components.

1. Cell mediated immunity (CMI).

2:. Humoral immunity (antibodies)

(I) Macrophages. Constituent of the M. P. S. These engulf the antigenic material.

(i) Most of the engulfed antigen is destroyed to' prevent a high dose paralysis of the Immune competent cells.

(ii) Some of it persists in the macrophage, retaining immunogenecity for continued stimulus to the immune system.

(iii)The antigenic information is passed on to  effectors cells. There are two proposed mechanisms for this:

(a) As messenger RNA with code for the specific antibody.

(b) As antigen-RNA complexes.

(2) Lymphocytes. There are 2 main classes recognized by surface characteristics.

(A) T-Lymyhocytes (thymus dependant) :- These are responsible for cellular immunity . On exposure to antigen 

• They transform to immunoblasts  which divide to form the effectors cells.
• They secrete lymphokines These are
  • Monocyte migration inhibition factor
  • Macrophage activation factor
  • Chemotactic factor
  • Mitogenic factor
  • Transfer factor
  • Lymphotoxin which kills target cell
  • Interferon.
  • Inflammatory factor which increases permeability. .
• Some remain as 1onglived memory cell for a  quicker recognition on re-exposure
• They also modify immune response by other lymphocytes in the form of “T – helper cells “ and “T-suppressor” cells
• They are responsible for graft rejection

(B) B-Lymphocytes (Bursa dependent). In birds the Bursa of Fabricious controls

these cells. In man, its role is taken up by," gut associated lymphoid tissue)

(i) They are responsible for antibody synthesis. On stimulation they undergo blastic transformation and then differentiation to plasma cells, the site of immunoglobulin synthesis.

(ii) They also form memory cells. But these are probably short lived.

(C) In addition to T & B lymphocytes, there are some lymphocytes without the surface markers of either of them. These are 'null' cells-the-natural Killer (N,K.) cells and cells responsible for antibody dependent cellular-cytotoxicity.

(3) Plasma cells. These are the effectors cells of humoral immunity. They produce the immunoglobins, which are the effector molecules.

Osteopetrosis (Albers-Schönberg disease or marble bone disease) 

is a group of rare genetic disorders characterized by reduced osteoclast-mediated bone resorption and therefore defective bone remodelling. The bones are solid and heavy with no medullary canal, long ends are bulbous, small neural foramina compress nerves. The affected bone is grossly dense but fractures occur readily like a piece of chalk. 

Patients frequently have cranial nerve compressions by the surrouding bone, and recurrent infections. The latter is attributable to diminished hematopoiesis resulting from reduced marrow space with impressive hepatosplenomegaly due to extramedullary hematopoiesis 
 
a. Caused by abnormal osteoclasts. This results in defective bone remodeling (i.e., abnormally low bone resorption) and increased bone density, which may invade into bone marrow space.
b. Causes severe defects in infants, including:
(1) Anemia and infections—caused by decreased bone marrow.
(2) Blindness, deafness, paralysis of facial muscles—caused by the narrowing of cranial nerve foramina.
(3) Is life-threatening.
(4) Oral findings include delayed eruption of teeth.
c. Disease is less severe in adults

 IMMUNO PATHOLOGY
Abnormalities of immune reactions are of 3 main groups
- Hypersensitivity,
- Immuno deficiency,
- Auto immunity.
Hypersensitivity (ALLERGY)
This is an exaggerated or altered immune response resulting in adverse effects

They are classified into 4 main types.

I. Type I-(reaginic, anaphylactic). This is mediated by cytophylic Ig E antibodies, which get bound to mast cells. On re-exposure, the Ag-Ab reaction occurs on the mast cell surface releasing histamine.

Clinical  situations

I. Systemic anaphylaxis, presenting with bronchospasm oedema hypertension, and even death.
2. Local (atopic) allergy.
- Allergic rhinitis (hay fever)
- Asthma
- Urticaria.
- Food allergies.

2. Type II. (cytotoxic). Antibody combines with antigen present on-cell surface. The antigen may be naturally present on the surface or an extrinsic substance (e.g.drug) attached to cell surface.

The cell is then destroyed by complement mediated lysis (C89) or phagocytosis of the antibody coated cell. 

Clinical situations

- Haemolytic anemia.
- Transfusion reaction
- Auto immune haemolytic anemia.
- Haemolysis due to some drugs like Alpha methyl dopa

2. Drug induced thrombocytopenia (especially sedormid).
3 Agranulocytosis due to sensitivity to some drugs.
4 Goodpasture’s syndrome-glomermerulonephritis due to anti basement membrane antibodies.

3. Type III. (Immune complex disease). Circulating immune complexes especially small soluble complexes tend to deposit in tissues especially kidney, joints, heart and arteries.

These then cause clumping of platelets with subsequent release of histamine. and serotonin resulting in increased permeability. Also, complement activation occurs which being chemotactic results in aggregation of polymorphs and necrotising vasculitis due to release of lysosmal enzymes

Clinical situations

- Serum sickness.
- Immune complex glomerulonephritis.
- Systemic lupus erythematosus.
- Allergic alveolitis.
- Immune based vasculitis like
    o    Drug induced vasculitis.
    o    Henoch – Schonlein purpura

4. Type IV. (Cell mediated). The sensitized lymphocytes may cause damage by cytotoxicity or by lymphokines and secondarily involving macrophages in the reaction.

Clinical situations

I. Caseation necrosis in tuberculosis.
2. Contact dermatitis to
    - Metals.
    - Rubber.
    - Drugs (topical).
    - Dinitrochlorbenzene (DNCB).
    
5. Type V. (stimulatory) This is classed by some workers separately and by other with cytotoxic type (Type II) with a stimulatory instead of toxic effect

Clinical Situations :
LATS (long acting thyroid stimulator) results in thyrotoxicosis (Grave’s disease)
 

Cytopathologic techniques

Cytopathology is the study of cells from various body sites to determine the cause or nature of disease.

Applications of cytopathology:

1. Screening for the early detection of asymptomatic cancer

2. Diagnosis of symptomatic cancer

3. Surveillance of patients treated for cancer

Cytopathologic methods

There are different cytopathologic methods including:

1. Fine-needle aspiration cytology (FNAC) -In FNAC, cells are obtained by aspirating the diseased organ using a very thin needle under negative pressure.

Superficial organs (e.g. thyroid, breast, lymph nodes, skin and soft tissues) can be easily aspirated.

Deep organs, such as the lung, mediastinum, liver, pancreas, kidney, adrenal gland, and retroperitoneum are aspirated with guidance by fluoroscopy, ultrasound or CT scan.

1. Exfoliative cytology

Refers to the examination of cells that are shed spontaneously into body fluids or secretions. Examples include sputum, cerebrospinal fluid, urine, effusions in body cavities (pleura, pericardium, peritoneum), nipple discharge and vaginal discharge.

1. Abrasive cytology

Refers to methods by which cells are dislodged by various tools from body surfaces (skin, mucous membranes, and serous membranes). E.g. preparation of cervical smears with a spatula or a small brush to detect cancer of the uterine cervix at early stages.

Abnormalities in chromosome number
Trisomy 21 (Down syndrome)
(1) The most common chromosomal disorder.
(2) A disorder affecting autosomes. It is generally caused by meiotic nondisjunction in the mother, which results in an extra copy of chromosome 21 or trisomy 21.
(3) Risk increases with maternal age.
(4) Clinical findings include mental retardation and congenital heart defects. There is also an increased risk of developing acute leukemia
and an increased susceptibility to severe infections.
(5) Oral findings include macroglossia, delayed eruption of teeth, and hypodontia.

Trisomies 18 and 13
(1) Trisomy 18 (Edwards syndrome):
characterized by an extra copy of chromosome 18. Oral findings include micrognathia.
(2) Trisomy 13 (Patau’s syndrome): characterized by an extra copy of chromosome 13. Oral findings include cleft lip and palate.
(3) Meiotic nondisjunction is usually the cause of an extra chromosome in both of these trisomies.
(4) Clinical findings for both of these trisomies are usually more severe than trisomy 21. Most children with these diseases die within months after being born due to manifestations such as congenital heart disease.

Klinefelter’s syndrome
(1) One of the most common causes of male hypogonadism.
(2) Characterized by two or more X chromosomes and one or more Y chromosomes. Typically, there are 47  chromosomes with the karyotype of XXY.
(3) The cause is usually from meiotic nondisjunction.
(4) Clinical findings include atrophic and underdeveloped testes, gynecomastia, tall stature, and a lower IQ.

Turner’s syndrome
(1) One of the most important causes of amenorrhea.
(2) Characterized by having only one X chromosome, with a total of 45 chromosomes and a karyotype of XO.
(3) Clinical findings include underdeveloped female genitalia, short stature, webbed neck, and amenorrhea. Affected females are usually
sterile. Unlike other chromosomal disorders, this one is usually not complicated by mental retardation.

Treacher Collins syndrome (mandibulofacial dysostosis)
(1) Genetic transmission: autosomal dominant.
(2) A relatively rare disease that results from abnormal development of derivatives from the first and second branchial arches.
(3) Clinical findings include underdeveloped zygomas and mandible and deformed ears. Oral findings include cleft palate and small or absent parotid glands.