Response to cellular injury

Question 1

What does cellular injury lead to?

Answer 1

Repair and regeneration with organisation

Question 2

The outcome of cellular injury is either:

Answer 2

1. Complete restitution with no or minimal residual effect. The end result is as if no damage occurred, or
2. Organisation and healing which entails an inflammatory response with regeneration of destroyed structures. It results in scarring.

Question 3

The capability of cells to _____________ is the most important factor influencing consequences of injury

Answer 3

replicate

Question 4

Cells are classified according to their ____________________.

Answer 4

Potential for renewal

Question 5

Which two cell types can regenerate? (They replicate from stem cells)

Answer 5

Labile cells
Stable cells

Question 6

LABILE CELLS

Answer 6

• good capacity to regenerate i.e. high reproductive capacity
• divide actively throughout life to replace lost cells

e.g. cells of the epidermis and gastrointestinal mucosa, cells lining the surface of the genitourinary tract, and hematopoetic cells of the bone marrow

Question 7

STABLE CELLS

Answer 7

• divide slowly under physiological conditions
• capable of rapid division when activated or following injury

e.g. hepatocytes, renal tubular cells, parenchymal cells of many glands, and numerous mesenchymal cells (e.g. smooth muscle, cartilage, connective tissue, endothelium and osteoblasts)

Question 8

PERMANENT CELLS

Answer 8

• considered to be incapable of effective division and regeneration (new evidence involving stem cells challenges this view)
• replaced by scar tissue (typically fibrosis; gliosis in the central nervous system) after irreversible injury and cell loss

e.g. neurons, skeletal muscle and myocardial cells

Question 9

Complete healing depends on:

Answer 9

• Type
• Extent
• Duration of injury
• Regenerative capacity of cells affected

e.g. an acute episode of viral gastroententeritis causing sloughing of bowel epithelium. The epithelium is replaced rapidly with regenerated stem cell source.

Question 10

If the injury is too extensive or the harmful cause persists, then ________________________ will not be able to occur. This results in the formation of a ________________ after the process of _______________________.

Answer 10

regeneration; scar; organisation

Question 11

Example of complete restitution

Answer 11

Healing of a minor skin abrasion:

The scab, a layer of fibrin, protects the epidermis as it grows to cover the defect. The scab is then shed and the skin is restored to normal.

Question 12

Organisation

Answer 12

• organisation is the repair of specialised tissues by the formation of a: fibrous scar.
• ## starts with the production of granulation tissue and removal of dead tissue by phagocytosis

Question 13

Function of granulation tissue

Answer 13

• to fill the gap caused by cell injury
• it comprises: combination of inflammatory cells, connective tissue cells producing extracellular matrix and new vessels growing in capillary loops
• the name derives from the appearance of the base of a skin ulcer. When the repair process is observed, the capillary loops are just visible and impart of a granular texture.

Question 14

Granulation tissue

Answer 14

Capillary endothelial cells proliferate and grow into the area to be repaired. This process is referred to as angiogenesis.

Question 15

Wound contraction

Answer 15

• is important for reducing the volume of tissue for repair; the tissue defect may be reduced by 80%. Results from the contraction of myofibroblasts in the granulation tissue
• collagen is secreted and forms a scar, replacing the lost specialised tissues

Question 16

Complications of wound contraction

Answer 16

• if the tissue damage is circumferential around the lumen of the tube such as the gut, subsequent contraction may cause stenosis (narrowing) or obstruction due to a structure.
• similar tissue distortion resulting in permanent shortening of a muscle —> contracture
• burns to the skin can be followed by considerable contraction, with resulting cosmetic damage and often impaired mobility
• myocardial contractility is also compromised by fibrosis left after myocardial scarring

Question 17

Stages in wound healing:

Answer 17

1. Bleeding into the wound from damaged blood vessels
2. Fibrin plug and initiation of epithelial proliferation
3. Influx of neutrophils and growth factor release triggers angiogenesis, forming granulation tissue. Re-epithelialisation progresses
4. Fibroblasts are recruited to secrete extracellular matrix, which replaces the granulation tissue as the epithelial surface heals
5. Vessel growth completes, and the ECM begins to mature
6. Over time, fibroblast numbers diminish and the ECM fully matures

Question 18

Skin injuries

Answer 18

Skin incision healed by first incision:

• As little or no tissue has been lost, the opposed edges of the incision are joined by a thin layer of fibrin, which is ultimately replaced by collagen covered by surface epidermis

Skin wound required by second intention:

• the tissue defect becomes filled with granulation tissue, which eventually contracts, leaving a small scar

Question 19

Injury in the GIT

Answer 19

The fate of an intestinal injury depends upon its depth.

Question 20

Mucosal erosion

Answer 20

• loss of part of the thickness of the mucosa
• viable epithelial cells are immediately adjacent to the defect and proliferate rapidly to regenerate the mucosa
• such an erosion can be re-covered in a matter of hours, provided that the cause has been removed
• notwithstanding this remarkable speed of recovery, it is possible for a patient to lose much blood from multiple gastric erosions before they heal
• if endoscopy (to determine the cause of haematemesis) is delayed, the erosions may no longer be present, and thus escape detection

Question 21

Mucosal ulceration

Answer 21

• the loss of the full thickness of the mucosa, and often the defect goes much deeper to penetrate the muscularis propria
• destroyed muscle cannot be regenerated, and the mucosa must be replaced from the margins
• damaged blood vessels will have bled and the surface will become covered by a layer of fibrin
• macrophages then remove any dead tissue by phagocytosis. Meanwhile, granulation tissue is produced in the ulcer base, as capillaries and myofibroblasts proliferate.
• the mucosa will also begin to regenerate at the margins and spread out on to the floor of the ulcer

Question 22

Injury in the bone

Answer 22

Immediately after a fracture, there will be haemorrhage within the bone from ruptured vessels in the marrow cavity. This collection of blood: HAEMOTOMA
–> this haemotoma at the fracture site facilitates repair by providing a foundation for the growth of cells

• initial phases of repair involve removal of necrotic tissue and organisation of the haemotoma. Necrotic tissue arises from accompanying dead fragments of bone, and soft tissue damage
• in the organising haemtoma, the capillaries will be accompanied by fibroblasts and osteoblasts. These deposit bone in an irregularly woven pattern.
• the mass of new bone, sometimes with islands of cartilage, is called: “callus.” Initially, a soft callus is formed The main purpose: to form anchorage between to two ends of the fracture site. As it calcifies, it is transformed into a bony callous, and when osteoid is deosited, woven bone is formed. Woven bone is subsequently replaced by more orderly lamellar bone; this in turn is gradually remodelled according to the direction of mechanical stress.

Question 23

Healing of a bone fracture

Answer 23

The haemotoma at the fracture site gives a framework for healing

• it is replaced by a fracture callus, which subsequently is replaced by lamellar bone, which is then remodelled to restore the normal trabecular pattern of the bone

Question 24

Problems with fracture healing

Answer 24

1. Movement: Movement between two ends slows down tissue union and prevents bone formation. Collagen is laid down instead to give fibrous union; this results in a false joint at the fracture site
2. Interposed soft tissue: Interposed soft tissues between the broken ends delay healing, increasing the risk of non-union.
3. Gross misalignment
4. Infection: infection at the fracture site will delay healing, but is not likely unless the skin over the fracture is broken; this is referred to as a “compound fracture.”
5. Pre-existing bone disease: If the bone broken was weakened by disease, the break is called a “pathological fracture.” Causes of a pathological fracture include: primary disorder of bone, or the secondary involvement of bone by metastatic neoplastic disease.

Question 25

Muscular injury

Answer 25

HYPERTROPHY: thickening of the heart muscle occurs when cardiac muscle mass increases due to prolonged and increased stress on heart.

Cardiac, skeletal and smooth muscle cells = permanent cells
- skeletal muscle: contains numerous “satellite cells” underneath basal lamina. These are mononucleated quiescent cells. When the muscle is damaged, these cells are stimulated to divide. After dividing, the cells fuse with existing muscle fibres, to regenerate and repair the damaged fibres. The skeletal muscle fibres themselves, cannot divide. However, muscle fibres can lay down new protein and enlarge (hypertrophy).

• cardiac muscle: Can also hypertrophy e.g. with chronic untreated hypertension leads to left ventricular hypertrophy. There are no equivalent to cells to the satellite cells found in skeletal muscle. Thus, when cardiac muscle cells die, they are not replaced. Damaged muscle is replaced by scar tissue.
• smooth cells: have greatest capacity to regenerate of all the muscle cell types. The smooth muscle cells themselves retain the ability to divide, and can increase in number.

Question 26

LIVER REPAIR

Answer 26

• hepatocytes, a stable cell population, have excellent regenerative capacity
• hepatic architecture cannot be satisfactorily reconsructed if severely damaged.
• conditions that result only in hepatocyte loss may be followed by complete restitution e.g. hepatitis A, whereas damage destroying both the hepatocytes and arcitecture may not, e.g. chronic alcoholic abuse
• if architecture is destroyed, the imbalance between hepatocyte regeneration and poorly reconstructed the architecture leads to cirrhosis
• CIRRHOSIS: a diffuse change in the liver structure, with the development of fibrous septa that sub-divide the parenchyma into nodules (usually irreversible)

Question 27

KIDNEY INJURY

Answer 27

• the kidney has an epithelium that can be regenerated but an architecture that cannot
• loss of tubular epithelium following an ischaemic episode or exposure to toxins => renal failure
• stable cells can regenerate to repopulate the tubules and enable normal renal function to return
• glomerular damage => to be permanent or resultb in glomerular scarring, with loss of filtration capacity
• similarly, interstitial inflammation is liable to proceed to fibrosis and, thus impaired re-absorption from tubules

Question 28

INJURY TO NEURAL TISSUE

Answer 28

• even though evidence suggests that adult nerve cells may have a low replicative capacity, there is no effective regeneration of neurons in CNS.
• glial cells, may proliferate in response to injury, a process referred to as: gliosis
  -peripheral nerve damage affects axons and their supporting structures, such as Schwann cells. If there is transection of the nerve, axons degenerate proximally for a distance of about one or two nodes; distally there is Wallerian degeneration followed by proliferation of Schwann cells in anticipation of axonal growth.
  -if there is good re-alignment of the cute ends, the axons may regrow down their previous channels (now occupied by proliferated Schwann cells); however, full functional recovery is unusual. When there is poor alignment or amputation of the nerve, the cut ends of the axons still proliferate, but in a disordered manner, to produce a tangled mass of axons and stroma called an amputation neuroma. Sometimes, these are painful and require removal.

Question 29

Modifying influences:

Answer 29

• Age
• Disorders of Nutrition
• Cushing’s syndrome and steroid therapy
• Diabetes and immunosuppressin
• Denervation

Question 30

Age

Answer 30

Injuries heal more rapidly in healthy children. Older people have less capacity to repair damaged tissue.

Question 31

Disorders of nutrition

Answer 31

• protein is needed for wound healing. Protein malunutrition impairs wound healing and increases the risk of infection
• Vit. C is needed to make collagen - shortage thereof leads to scurvy
• Neoplastic disorders - malignant neoplasms can lead to impaired wound healing

Question 32

Cushing’s syndrome and steroid therapy

Answer 32

• two effects on tissue injury due to immunosuppressin
• the consequences of injury and infection may be more severe
• steroids impair the formation of: granulation tissue
  : wound retraction

Question 33

Diabetes and immunosuppressin

Answer 33

• both increase susceptibility to infection with low virulence organisms
• Diabetes may influence polymorph function, occlude small blood vessels and cause neuropathy
• vascular distrubance
• good blood supply is needed for cellular function. Shortage impairs healing.

Question 34

Denervation

Answer 34

Can lead to severe damage due to absent normal reaction to trauma, and less awareness of infection and inflammation

Question 35

Ionising radiation of medical importance

Answer 35

ELECTROMAGNETIC RADIATION: produces ions which require a photon of high energy and thus short wavelength. If the photon is emitted by a machine, the radiation is called an x-ray.

• when a beam of X radiation is shot through the patient’s body, the rays that pass through are recorded by a detection device
• the image produced results from the variable absorption of the X-ray photons by the various structures of the body. Bones absorb more photons than soft tissues so they cast sharp shadows, with the other body compartments producing shadows of less intensity.
• if emitted as a result of disnintegration of an unstable atom, it is referred to as a gamma ray. Gamma ray emission is continuous, so protection requires a physical barrier. Gamma rays can be used to induce cell injury and death in high doses. Thus good for use in radiation oncology.

Question 36

Radiation in a nutshell

Answer 36

• exposure to ionizing radiation causes: cell damage to living tissue and organ damage. Labile and germ cells are affected most severely. In high acute doses, it will result in radiation burns and radiation sickness, and lower level doses over a protracted time can result in carcinogenesis.
• thus in view of harm of ionisation radiation, it is important that it is used safely and only when there are no suitable alternatives
• MRI and ultrasound safer alternatives than children’s over-exposure to X-rays and CT scans
• radotherapy for treating one tumour type can cause secondary complications such as fibrosis and increase risk for secondary tumours e.g. radiation induced angiosarcooma after treating breast carcinoma.