HSC2001 – Pathophysiology & Pharmacology – Tissue Healing and Inflammation
Pathophysiology is the study of underlying changes in the body’s physiology and function, on a molecular, cellular and organism level, that result from disease or injury.
In this module, we will explore pathophysiology in three levels, having a foundational understanding of:
The 8 body systems that we will focus on are:
And the two main scopes of study are immunopathology, with a focus on rheumatology, and infectious diseases.
Combined in a single diagram, the scope of the module looks like this:
Notice that the 8 body systems are not the exhaustive set of systems represented by the human body. We have decided to focus on the systems with diseases that are locally prevalent. And likewise for oncology, where we focus on the more prevalent cancers like breast, lung and colorectal.
We will use several tools to gauge the specific diseases, not just the pathophysiology, but also the etiology, epidemiology, and how it affects quality of life. The DALY score (Disability Adjusted Life Years) is used to gauge this; the value of keeping the patient alive with the disease.
Inflammation and Tissue Healing
There are a few different descriptions of a disease. The following example is illustrated with a specific case of cholecystitis, which is inflammation of the gallbladder.
The body's defense system is divided into the non-specific (generic / general) defense system and the specific defense system.
Mechanical barriers include the skin, saliva, and tears produced by the tear ducts. Non-specific phagocytosis is not meant to target anything in particular, but rather, engulf anything foreign in the bloodstream. Inflammation is induced by the chemicals secreted by the mast cells. Interferons are a group of signaling proteins released by a host cell’s response to the presence of several viruses. Typically, a virus infected cell will release interferons, that causes nearby cells to heighten their anti-viral defenses.
Humoral immunity is the aspect of immunity that is mediated by the macromolecules found in extracellular fluids such as secreted antibodies, complement proteins and some antimicrobial peptides. Cell mediated immunity, on the other hand, is an immune response that does not involve antibodies, but rather, the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.
When a normal cell faces stress, it will try to adapt. If it were unable to do so, the adaptation will manifest into an injury. If the injury were mild and transient, then it is known as a reversible injury and can be recovered from. If the injury is severe and progressive, then the injury is irreversible, and the cell will face death, either through apoptosis or necrosis.
This can be illustrated with the diagram below:
There are many causes of cell injury, and can occur as a result of a myriad of insults:
Ischemia or infarction: Inadequate blood supply will hinder the removal of toxic metabolites from cells
Infection: From microorganisms like bacteria, viruses or parasites
Immune / Allergic reactions: Underregulation or overregulation of certain hormones can lead to autoimmune reactions or hypersensitivity reactions
Direct physical damage: Thermal, mechanical pressure, tear, radiation, electricity
Chemical factors: These can be exogenous, which means the chemical starts off outside the body, or endogenous, where the body produces chemicals which are then translocated such that they exert a toxic effect
Genetic factors: Refers to mutations and neoplasms
Nutritional factors: Cachexia can result in cell injury
Fluid / electrolyte imbalance
Foreign bodies: like splinters and glass, can result in cell injury
There are six types of cellular adaptation:
Hyperplasia – Increase in number of cells
Hypertrophy – Increase in size of cells
Atrophy – Decrease in size or number of cells
Dysplasia – Abnormal change in size, shape, and elevated mitosis
Metaplasia – Abnormal change in morphology and function
Neoplasia – A malignant change that disrupts the basement membrane
There are four overlapping but well-defined phases of repair in acute wound healing. These four stages are:
Hemostasis
Inflammation
Proliferation
Remodelling
These processes can be illustrated with the following diagram:
Inflammation is a protective response involving host cells, blood vessels and other chemical mediators, intending to eliminate the initial cause of injury and necrotic cells and tissue from the original insult, and to initiate the process of repair.
Conditions with inflammation are usually suffixed with the -itis suffix:
Pancreatitis (Pancreas)
Hepatitis (Liver)
Appendicitis (Appendix)
Myositis (Muscles)
Arthritis (Joints)
It is a normal protective mechanism in pathophysiology, and the inflammatory response will stop once the injurious agent is removed. Inflammation is not the same as an infection.
The first steps of the inflammatory response is tissue injury, which causes the release of chemicals like bradykinin and histamine. This stimulates pain receptors and on a vascular level, dilates the capillaries, making them more permeable. On a cellular level, neutrophils and macrophages leave the bloodstream by chemotaxis and engulfs microbes by phagocytosis.
The four cardinal signs of inflammation are:
Rubor – Redness / Erythema, as a result of vasodilation
Calor – Heat, as a result of vasodilation
Tumor – Swelling, as a result of capillary permeability and protein leakage
Dolor – Pain, as a result of nerve irritation by chemical mediators, especially bradykinin
Combined with these four cardinal signs, there may also be a temporary loss of function to the inflamed site. On a physiological level, this is to discourage use of the body part, and its intent is to aid recovery.
Additionally, there may be an induced systemic effect, including low grade fever, malaise, or general feeling of unwell-ness, fatigue, headache and anorexia, brought on by the loss of appetite.
The inflammatory process is basically the same regardless of the cause. The timing, however, varies with the specific cause. Inflammation may develop immediately and last only a short time, or it may have delayed onset like sunburns, or it may be more severe and prolonged. The severity of the inflammation also varies with the specific cause and duration of exposure.
When tissue injury occurs, the damaged mast cells and platelets release chemical mediators including histamine, serotonin, prostaglandins, and leukotrienes into the interstitial fluid and blood. These chemicals affect blood vessels and nerves in the damaged area. Cytokines serve as communicators in the tissue fluids, sending messages to lymphocytes and macrophages, the immune system, or the hypothalamus to induce fever.
Chemical mediators such as histamine are released immediately from granules in mast cells and exert their effects at once. Other chemical mediators such as leukotrienes and prostaglandins must be synthesised from arachidonic acid in mast cells before release, and therefore, are responsible for later effects, prolonging the inflammation process. Many of these chemicals also intensify the effects of the other chemicals in the response. Many anti-inflammatory drugs and antihistamines reduce the effects of some of these chemical mediators.
A summary of the functions of chemical mediators of inflammation is shown in the table below:
Although nerve reflexes at the site of the injury cause immediate transient vasoconstriction, the rapid release of chemical mediators result in local vasodilation which causes hyperaemia, an increased in bloodflow to the area. Capillary membrane permeability also increases, allowing plasma proteins to move into the interstitial space along with more fluid. The increased fluid dilutes any toxic material at the site, while the globulins serve as antibodies, and fibrinogen forms a fibrin mesh around the area in an attempt to localise the injurious agent. Any blood clotting will also provide a fibrin mesh to wall off the area. Vasodilation and increased capillary permeability make up the vascular response to tissue injury.
During the cellular response, leukocytes are attracted by chemotaxis to the area of inflammation as damaged cells release their contents. Several chemical mediators at the site of injury act as potent stimuli to attract leukocytes. The role of each leukocyte is summarised in the following diagram:
First, neutrophils (polymorphonuclear leukocytes) and later monocytes and macrophages collect along the capillary wall and then migrate out through wider separations in the wall into the interstitial area. This movement of cells is termed diapedesis. There, the cells destroy and remove foreign material, microorganisms, and cell debris by phagocytosis, thus preparing the site for healing. When phagocytic cells die at the site, lysosomal enzymes are released and damage the nearby cells, prolonging inflammation. If an immune response or blood clotting occurs, these processes also enhance the inflammatory response.
As excessive fluid and protein collects in the interstitial compartment, bloodflow in the area decreases as swelling leads to increased pressure.
The summarised steps to wound repair is as follows:
Bacteria and other pathogens enter the wound
Platelets from blood release blood-clotting proteins at wound site
Mast cells secrete factors that mediate vasodilation and vascular constriction. Delivery of blood, plasma, and cells to injured area increases
Neutrophils secrete factors that kill and degrade pathogens
Neutrophils and macrophages remove pathogens by phagocytosis
Macrophages secrete hormones called cytokines that attract immune system cells to the site and activate cells involved in tissue repair
Inflammatory response continues until the foreign material is eliminated and the wound is repaired
Inflammation can be divided into acute and chronic inflammation.
Acute inflammation is a healthy response that serves to protect and repair the body from something damaging. It is characterised by pain, swelling, redness and warmth in the injured area.
Chronic inflammation follows the acute episode of inflammation with continued tissue destruction. Compared to acute inflammation, chronic inflammation has:
lesser swelling and exudate
presence of more lymphocytes, macrophages and fibroblasts
more severe tissue destruction
more collagen & scar tissue.
Diagnostic Tests for Inflammation
A variety of diagnostic tests can be performed to test for inflammation.
Leukocyte count will be elevated throughout the bloodstream, especially neutrophils.
The differential count can be taken, as the proportion of each type of WBC will be altered. This can be used to distinguish between a viral and bacterial infection. Allergic reactions will exhibit an elevated eosinophil count. A pyogenic bacteria infection will elevate neutrophil count, which contributes to pus production. A viral infection will involve more lymphocytes, and a parasitic infection will produce more basophils.
Cell enzymes are released from necrotic cells and enter tissue fluids and blood. They may indicate the site of inflammation. Some helpful enzymes include Isoezyme, CK-MB (Creatine-Kinase for Muscle/Brain), specific for myocardial infarction; and the ALT (Alanine Aminotransferase), which is specific for the liver.
Plasma proteins can be measured as there are elevated levels of fibrinogen and prothrombin in the blood. C-reactive protein is a protein not normally in the blood, but appears with acute inflammation and necrosis within 24 – 48 hours. The Erythrocyte Sedimentation Rate (ESR) can also be measured, as plasma proteins increase the ESR. These 3 methods of measuring blood changes are known as the non-specific changes of inflammation, and are unable to tell the cause or site of the inflammation. Rather, they serve as screening and monitoring parameters.
Complications
There are some potential complications that may arise as a result of inflammation. They are:
Infection
Skeletal muscle spasm
Deep ulceration
Infections can arise because microorganisms and other pathogens can more easily penetrate edematous tissues. Some microbes resist phagocytosis, and the inflammatory exudate actually provides an excellent growth medium for the microorganisms.
Skeletal muscle spasms may be initiated by inflammation, and is a protective response to pain, discouraging use of that particular muscle.
Deep ulcers may result from severe or prolonged inflammation, and can be caused by cell necrosis and lack of cell regeneration that causes erosion of the tissue. This can lead to complications like perforation of viscera, which increases mortality, or extensive scar tissue formation, like keloids.
Management
The main treatment to offer for inflammation is given by the acronym RICE.
Rest
Ice
Compress
Elevate
Doctors may also involve certain drugs used to treat inflammation.
Glucocorticoids decrease capillary permeability and enhance epinephrine and norepinephrine. Some examples are Prednisone and Dexamethasone.
Factors affecting healing
As long as the inflammation does not progress to a chronic stage, it has the potential to recover. Here are some factors that affect healing, and whether they promote or delay healing.
