31 Cell Damage, Acute and Chronic Inflammation, Blood Test Serum Markers, Cell Proliferation, Tissue Repair and Possible Complications

Cell Damage

Cells can be damaged by physical or mechanical stresses (e.g. blunt trauma, cuts, surgical incisions).  Cells can also be damaged by pathogens (e.g. bacteria, viruses, protozoa, helminths, fungi and prions) and pathogenic enzymes and toxins.  Cells can be damaged by lack of oxygen, waste accumulation, and excessive heat or cold temperatures.  Auto-immune diseases and cancers can cause cellular damage.  Cells can also be damaged by electrical burns, acids, bases, radiation, toxic endogenous or exogenous chemicals, free radicals, (e.g. Reactive Oxidative Species, HO₂, OH^*, O₂^*),

Diagnostic Tests – Blood Tests and Serum Markers  

Often changes in the blood can yield diagnostice clues as to the cause or extent of cellular damage that has occurred.

For example, damaged cells release cytokines that stimulate the inflammatory response.  As a result there is an increase in inflammatory plasma proteins (e.g. prothrombin, fibrinogen, C-reactive proteins, and plasminogen).

In addition to inflammatory markers, a rise in specific antibodies occurs during an infection, as does the concentration of complement proteins.   The proportions of WBCs can be altered as well depending on the type of infection.  Neutrophilia (increased neutrophil counts) often occurs with bacterial infections.  Eosinophilia (increased eosinophil counts) often occurs with helminth infections.  Lymphocytosis (increases in NK, T, and B lymphocytes) occurs with viral infections

Damaged cells often release cellular content that can give clues as to what types of cells have been damaged.  For example damaged hepatocytes (liver cells) release liver enzymes (e.g. ALT, GGT, and AST) into the bloodstream.  Heart cells that are damaged in a myocardial infarction release cellular proteins (e.g. cardiac troponin, actin, myosin and creatine kinase) into the bloodstream.  Monitoring specific cellular enzyme and protein concentrations in the blood helps to inform the level and duration of the damage that has occurred to specific tissues in the body.

Acute Inflammation and Preparation for Healing

As mentioned in previous sections, tissue damage always results in inflammation.  The steps involved are as follows:

1. Cells that are damaged release cellular contents (e.g. ADP, K⁺, proteins and enzymes) and sometimes cytokines which stimulates the activity of macrophages and mast cells.  Macrophages phagocytose debris and infecting pathogens (if present) as well as release chemokines to induce the chemotaxis and recruitment of other WBCs.  Mast cells degranulate to release pro-inflammatory cytokines (e.g. histamine, bradykinin, and prostaglandins).  Cells that are damaged are not functional, so loss of function of this tissue will occur until healing (if possible) occurs
2. The pro-inflammatory cytokines bind to receptors on blood vessel walls and induce vasoconstriction as well as increased capillary permeability.  These cytokines can also trigger nociceptors resulting in pain sensations.  Leaked blood can also stimulate nociceptors.  Activated WBCs and some infectious agents release pyrogens as well which may give rise to fever.
3. The resulting increase in blood flow makes the tissue warm and red.  The increase in plasma fluid entering the tissue bed results in swelling and pain.  The leaked plasma fluid contains platelets and plasma proteins that assist with the immune response (e.g. fibrinogen, complement proteins, C-reactive proteins).  Fibrin mesh and clots help to contain the area and phagocytes remove cellular debris and any pathogens.  There is pain or swelling in a joint, muscle or bone, it may impede movement until healing occurs.
4. The WBCs that often migrate to the area include neutrophils, eosinophils, macrophages, dendritic cells, and NK cells (Natural Killer lymphocytes.  WBCs remove infectious agents, toxins, and debris.
5. At the same time platelets and tissues release growth factors to stimulate mitosis of replacement tissue cells.  Fibroblasts are abundant in the connective tissue throughout the body and produce collagen to help bind tissue together.  At this point in time, when healing has begun there are three possible outcomes.

Healing

1. Resolution:  It may be that the damaged cells do not die, and recover.  In this case, the term resolution is used and leads to return to full function.
2. Regeneration:  If the tissue is small and involves cell types that are readily able to regenerate, tissue stem cells will produce daughter cells through mitosis that lead to a replacement of lost tissue with the exact same types of cells.  This is termed regeneration.  Many types of epithelial cells, connective tissue cells, and even liver cells are very regenerative.
3. Replacement:  Cardiac muscle cells, skeletal muscle cells, kidney cells, brain and spinal cord neurons and some areas of cartilage are not very regenerative.  In the case where damage has occured to cell types that are not regenerative or if the wound or damage is signicant, it may be that an abundance of collagen and other cell types (e.g. fibroblasts) is required to replace the lost tissue forming what is known as scar tissue.  This process is termed fibrosis and involves the permanent loss of functional tissue.

During the healing process, capillaries become less permeable, and blood vessel diameter returns to normal.  WBCs become inactivated and fibrin mesh and clots are enzymatically cleaved, dissolved and removed.  The excess fluid in the interstitial space is absorbed by lymph vessels and returned to the bloodstream.  The signs of inflammation (redness, warmth, swelling and pain) all diminish.

Possible Complications of Tissue Damage and Inflammation

Possible complications of tissue damage and inflammation include the following:

1. Chronic Inflammation:  If the cause of damage is not removed (e.g. many auto-immune diseases), the perpetual damage may lead to more and more damage and activated WBCs which can cause collateral damage, delay healing and lead to fibrosis (permanent scarring and loss of functional tissue).
2. Infection:  If the wound is exposed to the external environment, microorganisms (even members of one’s normal flora) can become opportunistic and cause infection and therefore more damage.
3. Deep ulcers:  Damage to gastric mucosa can allow for gastric acids to erode underlying tissue and damage blood vessel resulting in severe and prolonged inflammation, bleeding, necrosis, infection, possible loss of functional tissue, and fibrosis.
4. Skeletal Muscle Spasms: can occur as a protective response to pain during sprains (damage to ligaments) and strains (damage to muscle or tendon).  Spasms that occur in bone fractures can force movement of broken bone ends resulting in shearing of tissue.  (Note:  Temporary muscle spasms (e.g. charley horse) during excessive exercise are different in that the cause is thought to be not enough blood flow, cellular dehydration, and/or electrolyte depletion).
5. Peripheral Nerve damage: can lead to permanent or temorary loss of sensation, paresthesias if damage is to sensory nerves and muscle weakness or paralysis if motor neurons are affected.  If peripheral nerve cells recover, function may be regained.  Loss of brain or spinal cord nerves is permanent and can lead to permanent losses of function – though some brain plasiticty may occur through rehabilitation.
6. Obstruction:  Swelling in the esophagus can lead to problems swallowing.  Swelling affecting the bronchioles, bronchi, or other parts of the respiratory tract can lead to problems breathing and potentially can affect gas exchange abilities of the lungs.
7. Increased Intracranial Pressure (ICP):  Swelling in the brain or cranial meninges can lead to increased intracranial pressures which can be fatal due to the pinching off of capillaries and reduced blood flow.
8. Myositis Ossificans:  This refers to the calcification that can occassionally occur within injured muscles, most commonly the arm or thigh muscles (e.g. quadriceps).  Risk factors include deep contusions that occur with contact sports (e.g. American football).  The pathogenesis of calcification is unclear, but is likely linked to large reserve of available calcium in skeletal muscles tissues, as well as inappropriate differentiation of local stem cells into osteoblasts.  Prevention may be assisted by treating deep contusions promptly with RICE (Rest, Ice, Compression, and Elevation).

Chronic Inflammation

Chronic inflammation can follow an acute episode of inflammation if the source of irritation is not entirely removed.  It may be that the tissue continues to exposed to damage from any of the following:  an infection (pathogen or pathogenic toxins), smoking, ingested or inhaled environmental pollutants, cancer, or chronic diseases such as diabetes, auto-immune diseases (e.g. Rheumatoid Arthritis, Systemic Lupus Erythematosus), and chronic diseases of the lungs, heart, kidneys, liver, digestive system, etc..

Chronic inflammation defers from acute inflammation in that there is:

1. Less swelling and exudate
2. More angiogenesis
3. More lymphocytes, macrophages, & fibroblasts are present
4. Continued tissue destruction
5. More collagen produced → fibrous scar tissue (fibrosis)
6. Possible formations of Granulomas (=small mass of cells with a necrotic center, covered by connective tissue) which are long lasting.  Granulomas may develop in rheumatoid arthritis and osteoarthritis, or  around a foreign object (possibly involving an abscess), or at a site of chronic infection such as tuberculosis.