Basis Mechanism Involved in Inflammation

Chapter 3

BASIC MECHANISM INVOLVED IN THE PROCESS OF INFLAMMATION, REPAIR AND ATHEROSCLEROSIS 

 Introduction  

• Inflammation is a critical homeostatic process that is activated by cellular injury regardless of the mechanism of that injury. Inflammation is essentially local in nature, although cellular mediators released during inflammation may initiate systemic responses as well. Systemic inflammatory response syndrome is the most extreme form of inflammatory response and may be life threatening in critically ill patients. This syndrome nearly always occurs in the setting of systemic infection and is termed as sepsis.

• Inflammation is defined as "the local response of living mammalian tissues to injury due to any agent". It is a body defense reaction in order to eliminate or limit the spread of injurious agent, followed by removal of the necrosed cells and tissues. Inflammatory processes are defensive or adaptive by design; however, they may contribute to distressing clinical manifestations of disease. At the same time, they are helping to eradicate it. Inflammation is the body’s attempt of self-protection; the aim being to remove harmful stimuli, including damaged cells, irritants, or pathogens and begin the healing process.

• Inflammation does not mean infection, even when an infection causes inflammation. Infection is caused by a bacterium, virus or fungus, while inflammation is the body’s response to it. Any injury, including an invasion by micro-organisms, causes inflammation in the affected area. Inflammation, a complex reaction, results from many different conditions. The damaged tissue releases substances that cause inflammation and that direct the immune system to do the following: 

1. Attack and kill any invaders. 
2. Dispose off dead and damaged tissue.  
3. Begin the process of repair. 

Etiology of Inflammation 

The agents causing inflammation may be as follows:

• Physical agents: Heat, cold, radiation and mechanical trauma.  

• Chemical agents: Organic and inorganic poisons. 

• Infective agents: Bacteria, virus and their toxins.

• Immunological agents: Cell mediated and antigen antibody reaction.

Cardinal Signs of Inflammation

The Roman writer Celsus in 1st Century A.D. named the famous four cardinal signs of inflammation:

• Rubor: Latin term for “redness”. This is because the capillaries are filled up with more blood than usual.

• Tumor: a Latin term for “swelling”. Caused by an accumulation of fluid. 

• Calor: Latin term for “heat”. As with the reason for the redness, more blood in the affected area makes it feel hot to the touch.

• Dolor: Latin term for “pain”. The inflamed area is likely to be painful, especially when touched. Chemicals that stimulate nerve endings are released, making the area much more sensitive.

Types of Inflammation

Depending upon the defense capacity of the host and duration of response, inflammation can be classified as acute or chronic.

• Acute inflammation: Acute inflammation is of short duration and represents the early body reaction and is usually followed by healing.Examples of diseases, conditions and situations which can result in acute inflammation include:

1. Acute bronchitis 
2. Sore throat from a cold or flu 
3.  A scratch/cut on the skin 
4.  Acute appendicitis 
5.  Acute dermatitis 
6.  Acute tonsillitis 
7.  Acute infective meningitis 
8.  Acute sinusitis

• Chronic inflammation: Chronic inflammation is of a longer duration and occurs either after the causative agents of acute inflammation persists for a long time or the stimulus that induces chronic inflammation from the beginning.

• The characteristic features of chronic inflammation are presence of chronic inflammatory cells such as lymphocytes, plasma cells and macrophages. Macrophage (phagocytic cells) derived from monocyte, walls of blood vessels and in loose connective tissue. They interact with lymphocytes to facilitate antibody production. Examples of diseases and conditions with chronic inflammation include:

1.   Asthma 
2.   Chronic peptic ulcer 
3.   Tuberculosis 
4.   Rheumatoid arthritis 
5.   Chronic periodontitis 
6.   Ulcerative colitis and Crohn’s disease 
7.   Chronic sinusitis 
8.   Chronic active hepatitis.

Basic Mechanism Involved in the Process of Inflammation

The changes in acute inflammation can be conveniently described under the following two headings.

Vascular Events 

Alteration in the microvasculature (arterioles, capillaries and venules) is the earliest response to tissue injury. These alterations include hemodynamic changes and changes in vascular permeability. 

•  Haemodynamic changes.
•  Altered vascular permeability.

Cellular Events 

• Exudation of leukocytes 
• Phagocytosis

 Haemodynamic changes: The earliest features of inflammatory response result from change in the vascular flow and caliber of small blood vessels in the injured tissue.The sequence of these changes is as under:

• Irrespective of the injury, immediate vascular response is the transient vasoconstriction of arterioles. With mild form of injury, the blood flow may be reestablished in 3-5 seconds. While with more severe injury, the vasoconstriction may last for about 5 min.

• Next follows persistent progressive vasodilatation which involves mainly the arterioles and lesser extents to venules and capillaries. This change is obvious within half an hour of injury. Vasodilatation results in increased blood volume in microvascular bed of the area, which is responsible for redness and warmth at the site of acute inflammation.

• Progressive vasodilatation in turn may elevate the local hydrostatic pressure resulting in transudation of fluid into the extracellular space. This is responsible for swelling at the local site of acute inflammation.

• Slowing or stasis is attributed to increased permeability of microvasculature that results in increased concentration of red cells and thus raised blood viscosity.

• Slowing or stasis is followed by leukocytes margination or peripheral orientation of leukocytes (mainly neutrophils) along the vascular endothelium. The leucocytes stick to the vascular endothelium briefly, and then move and migrate through the gaps between the endothelial cells into the extravascular space known as emigration.

Altered vascular permeability: In acute inflammation, normally nonpermeable endothelial layer of microvasculature becomes leaky. This is explained by one or more of the following mechanisms.

• The endothelial cells develop temporary gaps between them due to their contraction resulting in vascular leakiness. It is mediated by the release of histamine, bradykinin, and other chemical mediators. The response begins immediately after injury, is usually reversible and is for short duration (15-30 minutes).

• Direct injury to the endothelium causes cell necrosis and appearance of physical gaps at the sites of detached endothelial cells. Process of thrombosis is initiated at the site of damaged endothelial cells. The change affects all levels of microvasculature. The increased permeability may either appear immediately after injury and lasts for several hours or days (immediate sustained leakage) or may occur after a delay of 2-12 hours and last for hours to days (delayed prolonged leakage).

• Adherence of leukocytes to the endothelium at the site of inflammation may results in activation of leukocytes. The activated leukocytes release proteolytic enzymes and toxic oxygen species which may cause endothelial injury and increased vascular leakiness. This form of increased vascular leakiness affects only venules is a late response. 

Exudation of leukocytes: The escape of leukocytes from the lumen of microvasculature to the interstitial tissue is the most important feature of inflammatory response. In acute inflammation, polymorphonuclear neutrophils comprise the first line of body defense, followed later by monocytes and macrophages. The changes leading to migration of leukocytes are as follows: 

•  In the early stage of inflammation, the rate of flow of blood increases due to vasodilation. But subsequently there is slowing or stasis of blood stream. With stasis, changes in the normal axial flow of blood in the microcirculation takes place. The normal axial flow consists of central stream of cell comprised by leukocytes and RBC and peripheral cell free layer of plasma close to vessel wall. Due to slowing and stasis, the central stream of cells widens, and peripheral plasma zone becomes narrower because of loss of plasma by exudation. This phenomenon is known as 'margination'. As a result of redistribution, the neutrophils of the central column come close to the vessel wall, this is known as 'pavementing'

• Rolling and Adhesion: Peripherally marginated and pavemented neutrophils slowly roll over the endothelial cell lining of the vessel wall (Rolling phase). Neutrophils first roll among the surface of the endothelium in a process mediated by selectins, adhesion molecules that are expressed by endothelial cells and that bind reversibly to sites on the leukocyte membrane. Later, neutrophils become firmly adherent to the endothelium by binding of leukocyte adhesion molecules (Selectins, Integrins, Intercellular adhesion molecules-1, vascular cell adhesion molecule-1, platelet endothelial cell adhesion molecule-1 etc.)

• After sticking of neutrophils to endothelium, the former move along the endothelial cell is found where the neutrophils throw out cytoplasmic pseudopods. Subsequently the neutrophils are lodged between the endothelial cells and cross the basement membrane by damaging it locally with secreted collagenase and escape out into the extravascular space. This is known as 'transmigration'. The damaged basement membrane is repaired almost immediately, simultaneous to emigration of leukocytes, escape of RBCs through the gaps between the endothelial cells. It is passive phenomenon; RBCs being forced out either by raised hydrostatic pressure or may escape through the endothelial defects left after emigration of leukocytes.

Phagocytosis: It is defined as "the process of engulfment of solid particulate material by the cells". There are two main types of phagocytic cells:

• Polymorphonuclear neutrophils (PMN’s) which appear early in acute inflammatory response also called as microphage. Circulating Monocytes and fixed tissue mononuclear phagocytes are called as macrophages. Neutrophils and macrophages on reaching the tissue space produce several proteolytic enzymes lysozyme, protease, collagenase, elastase, lipase, proteinase, gelatinase and acid hydrolases. These enzymes degrade collagen and extracellular matrix that will kill bacteria.

• Biochemical mediators released during inflammation, intensify and propagate the inflammatory response. These mediators are soluble, diffusible molecules that can act locally and systemically. Mediators derived from plasma include complement and complement-derived peptides and kinins.

• Other mediators are derived from injured tissue cells or leukocytes recruited to the site of inflammation. Mast cells, platelets, and basophils produce the vasoactive amines serotonin and histamine.

• Histamine causes arteriolar dilation, increased capillary permeability, contraction of nonvascular smooth muscle, and eosinophil chemotaxis and can stimulate nociceptors (a sensory receptor for painful stimuli) responsible for the pain response. Its release is stimulated by the complement components C3a and C5a and by lysosomal proteins released from neutrophils. Histamine activity is mediated through the activation of one of four specific histamine receptors, designated H1, H2, H3 or H4, in target cells.

• Cyclooxygenase catalyzes the oxygenation of AA to form the cyclic endoperoxide PGG2, which is converted to the closely related PGH2. Both PGG2 and PGH2 are inherently unstable and rapidly converted to various prostaglandins, thromboxane A2 (TXA2), and prostacyclin (PGI1). In the vascular beds of most animals, PGE1, PGE2 and PGI1 are potent arteriolar dilators and enhance the effects of other mediators by increasing small-vein permeability. Other prostaglandins, including PGF2α and thromboxane, cause smooth muscle contraction and  

Healing

Regeneration: Injury to tissue may result in cell death and tissue destruction. Healing on the other hand is the body response to injury in an attempt to restore normal structure and function. The process of healing involves two distinct processes:

• Some parenchymal cells are short lived while others have long life span. In order to maintain proper structure of tissue, these cells are under the constant regulatory control of their cell cycle. These include growth factors such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor and endothelial growth factor.

• These cells continue to multiply throughout life under normal physiologic conditions. These include surface epithelial cells of epidermis, alimentary tract, respiratory tract, urinary tract, vagina, cervix, uterine endometrium, haemopoietic cells of bone.

• These cells decrease or lose their ability to proliferate after adolescence but retain the capacity to multiply in response to stimuli throughout adult life. These include parenchymal cells of organs like liver, pancreas, kidneys, adrenal and thyroid. Mesenchymal cells like smooth muscle cells, fibroblasts vascular endothelium bone and cartilage cells.

• These cells lose their ability to proliferate around the time of birth. These include neuron, skeletal muscle and cardiac cells. 

• When healing takes place by proliferation of parenchymal cells and usually result in complete restoration of the original tissues.

Repair: When the healing takes place by proliferation of connective tissue elements resulting in fibrosis and scarring. 

Repair is the replacement of injured tissue by fibrous tissue. These responses take place by participation of mesenchymal cells (consisting of connective tissue, stem cells fibrocytes and histocytes). The process of repair involves:

1. Granulation tissue formation 
2. Contraction of wounds.  

• The term granulation tissue derives its name from slightly granular and pink appearance of the tissue. Each granule corresponds histologically to proliferation of new small blood vessels which are slightly lifted on the surface by the covering of fibroblasts and young collagen.

• Formation of new blood vessels at the site of injury takes place by proliferation of endothelial cells from the margins of several blood vessels. Initially the proliferated endothelial cells are solid buds but within a few hours develop into the lumen and start carrying blood. The newly formed blood vessels are leakier, accounting for the edematous appearance of new granulation tissue. Soon these blood vessels differentiate into muscular arterioles, thin-walled venules and true capillaries.

• Collagen fibrils begin to appear by about 6 th day. As maturation proceeds, more and more of collagen is formed while the number of active fibroblasts and new blood vessels decreases. This results in formation of inactive looking scar.

• The wound starts contracting after 2-3 days and the process is completed by the 14th day. During this period the wound is reduced by approximately 80% of its original size. Contracted wound results in rapid healing since lesser surface area of the injured tissue has to be replaced.  

Atherosclerosis 

• Atherosclerosis (or arteriosclerotic vascular disease) is a condition where the arteries become narrowed and hardened due to an excessive buildup of plaque around the artery wall. Plaque is made up of fat, cholesterol, calcium, and other substances found in the blood. Over time, plaque hardens and narrows arteries. The disease disrupts the flow of blood around the body, posing serious cardiovascular complications. Atherosclerosis can lead to serious problems, including heart attack, stroke, or even death.

•  Healthy arteries are flexible and elastic, but over time, the walls in arteries can harden, a condition commonly called hardening of the arteries. The word atherosclerosis is of Greek origin and literally means focal accumulation of lipid and thickening of arterial intima (sclerosis [hardening.

• Atherosclerosis can affect any artery in the body, including arteries in the heart, brain, arms, legs, pelvis and kidneys. As a result, different diseases may develop based on which arteries are affected.

• All patients with atherosclerosis have arteriosclerosis, but those with arteriosclerosis might not necessarily have atherosclerosis. However, the two terms are frequently used with the same meaning.

Causes 

Atherosclerosis can begin in the late teens, but it usually takes decades to cause symptoms. Some people experience rapidlygressing atherosclerosis during their thirties, other during their fifties or sixties. Certain factors that can damage the inner area of the artery (endothelium) and can trigger atherosclerosis include:

•  High blood pressure 
•  High levels of cholesterol 
•  Smoking 
•  High levels of sugar in the blood

High triglycerides: Most fat in food and in the body takes the form of triglycerides. Blood triglyceride levels above 400 mg/dL have been linked to coronary artery disease in some people. Triglycerides, however, are not nearly as harmful as LDL cholesterol. 

Diabetes: Patients with poorly controlled diabetes, who frequently have excess blood glucose levels, are much more likely to develop atherosclerosis.

Genetics: People with a parent or sibling who has/had atherosclerosis and cardiovascular disease have a much higher risk of developing atherosclerosis than others.

Obesity: Excess weight increases the strain on the heart and increases the risk of developing atherosclerosis even if no other risk factors are present.  

Pathophysiology 

• Very low-density lipoprotein (VLDL) is produced by the liver and is changed into LDL by means of lipoprotein lipase. This process removes triglycerides from VLDL by hydrolysis, releasing fatty acids and leaving greater numbers of cholesterol, thus increasing the density of the molecule.

• The LDL crosses the endothelium and moves into the extracellular matrix where it is oxidized (by the aforementioned steps above), and forms oxidized LDL (OxLDL). 

• OxLDL is a cause of inflammation and signals monocytes (white blood cells) to enter the arterial wall to fix the inflammation. As monocytes enter the arterial wall, they transform into macrophages.

• Since the LDL is now oxidized due to aldehydes and lipid hydroperoxides, the modified apolipoprotein B in LDL attaches to macrophage scavenger receptor cells. At this stage, OxLDL has a very high number of cholesterol and cholesterol esters, since it lost antioxidants, triglycerides, and fatty acids in previous steps. Macrophages are supposed to remove cholesterol by use of high-density lipoprotein (HDL) particles, but if there is too much excess cholesterol, it causes the macrophages to enlarge and fill with lipids.

Symptoms

Atherosclerosis does not usually produce symptoms until blood circulation becomes restricted or blocked, leading to cardiovascular disease (CVD).

 The type of cardiovascular disease and its associated symptoms depends on, where the blockage occurs. The first signs of atherosclerosis can begin to develop during adolescence, with streaks of white blood cells appearing on the artery wall. The symptoms of the disease depend on, which arteries are affected.

If an aortic aneurysm ruptures, the person will experience a sudden and severe pain in the middle or side abdomen. In men, the pain can spread down into the scrotum (the sac containing the testicles)

Symptoms of a ruptured brain aneurysm usually begin with a sudden and severe headache, which has been described as like being hit on the head.

The arteries to the limbs, usually the legs, are blocked. The most common symptom is leg pain, either in one or both legs, usually in the calves, thighs or hips. The pain may be described as one of heaviness, cramp, or dullness in the leg muscles. Other symptoms may include.

•  Hair loss on legs or feet 
•  Male impotence (erectile dysfunction) 
•  Numbness in the legs 
•  The colour of the skin on the legs change 
•  The toenails get thicker 
•  Weakness in the legs

Diagnosis

Physicians may be able to make a diagnosis of atherosclerosis during a physical exam by means of a stethoscope and gentle probing of the arteries with the hand (palpation) to find signs of narrowed, enlarged or hardened arteries, including A weak or absent pulse below the narrowed area of artery. Decreased blood pressure in an affected limb. Whooshing sounds (bruits) over arteries, heard using a stethoscope. Signs of a pulsating bulge (aneurysm) in abdomen or behind knee. Evidence of poor wound healing in the area where blood flow is restricted.  

• Blood tests: Blood tests can detect increased levels of cholesterol and blood sugar that may increase the risk of atherosclerosis.

• Doppler ultrasound: It is a special ultrasound device (Doppler ultrasound) used to measure blood pressure at various points along arm or leg. These measurements can help doctor to measure the degree of any blockages, as well as the speed of blood flow in arteries. 

• Ankle-brachial index: This test can reveal the atherosclerosis in the arteries in legs and feet. Doctor may compare the blood pressure in ankle with the blood pressure in arm. This is known as the ankle brachial index. An abnormal difference may indicate peripheral vascular disease, which is usually caused by atherosclerosis.

• Stress test: A stress test, also called an exercise stress test, is used to gather information about how well heart works during physical activity. Because exercise makes heart pump harder and faster than it does during most daily activities, an exercise stress test can reveal problems within heart that might not be noticeable otherwise. An exercise stress test usually involves walking on a treadmill or riding a stationary bike while heart rhythm, blood pressure and breathing are monitored.

• Computerised tomography scan: A computerised tomography (CT) scan takes a series of X-ray images and uses a computer to assemble them into a more detailed three-dimensional image. It can often detect narrowing or hardening in the larger arteries.

Treatment

Lifestyle changes: The changes will focus on weight management, physical activity and a healthy diet. Doctor may recommend eating foods high in soluble fiber and limiting intake of saturated fats, sodium and alcohol.

Surgery: Severe cases of atherosclerosis may be treated by surgical procedures, such as angioplasty or coronary artery bypass grafting (CABG).

Balloon angioplasty, also known as percutaneous transluminal coronary angioplasty (PTCA), uses a small, thin tube (called a catheter) with a tiny balloon at its tip. The tube is inserted into the bloodstream through a large vessel in the arm or leg. By watching the progress of the tube on an X-ray, the cardiologist guides the tube into the heart, where it is inserted into a narrowed coronary artery. The tiny balloon is then inflated to widen the narrowed area. 

Endarterectomy: In some cases, fatty deposits must be surgically removed from the walls of a narrowed artery. When the procedure is done on arteries in the neck (the carotid arteries), it is called a carotid endarterectomy. 

Bypass surgery: In this, a graft bypass may be created using a vessel from another part of body or a tube made of synthetic fabric. This allows blood to flow around the blocked or narrowed artery.