Inflammation: Meaning and Purpose | Cell Injury | Organisms| Microbiology

In this article we will discuss about:- 1. Meaning and Purpose of Inflammation 2. Tissue Changes Associated with Inflammation 3. Mediators of Inflammatory Reactions 4. Leucocyte Recruitment and Activation 5. Leucocyte Functions during Inflammation 6. Healing and Tissue Repair.

Meaning and Purpose of Inflammation:

Inflammation is the body’s normal response to tissue injury, although it can sometimes lead to pathological tissue damage, including that seen in the hypersensitivity reactions.

The purpose of inflammation is:

1. To contain and control infection or injury;

2. To eliminate pathogens;

3. To initiate healing and tissue repair;

Inflammation represents a complex interaction of many components including blood vessels, tissue-derived mediators, while cells (leucocytes), fibroblasts, endothelial cells, epithelium, the coagulation and fibrinolytic systems, the kinin system and the component system.

Inflammation is characterized by local tissue signs, first described in about 30 BC by Celsus, which are tumour (swelling), rubor (redness), calor (heat) and dolor (pain). Systemic effects include fever, increased production of leucocytes by the bone marrow (leucocytosis) and increased synthesis of some plasma proteins by the liver. The tissue changes associated with the inflammation.

Tissue Changes Associated with Inflammation:

Inflammatory responses are classified as acute or chronic reactions, depending upon the histological and morphological features, although these are not always exclusive. The nature of the inflammatory response and its detailed appearance depend on the type of injury and the tissue involved.

For instance, acute inflammation in the skin has a different macroscopic appearance to that in internal organs or mucous membranes. Chronic inflammation sometimes follows acute inflammation if, for instance, the acute response fails to eliminate a pathogen. However, chronic inflammation can occur without an acute response.

i. Acute Inflammation:

The acute inflammatory response occurs rapidly (minutes to hours) after injury or infection. Initially, there is dilation of small blood vessels (venules and arterioles) with an increased local blood flow (hyperaemia), which then decreases or stops (stasis). The vessels become more permeable, leading to movement of blood plasma and platelets into the tissues (this is often referred as a serous exudate), causing oedema (an excess of intercellular fluid in the tissues).

A serous exudate below the epidermis is what causes a blister. Fibrinogen in the exudate is converted to fibrin, which is deposited and helps to localize tissue damage and control bleeding. Blood cells, especially neutrophils, migrate into the tissue. Sometimes, typically in response to pyogenic (pus-forming) bacterial infection, a purulent exudate or pus is formed, consisting of dead cells, neutrophils and bacteria.

When large numbers of neutrophils are present the pus appears yellow or green, because of the presence of myeloperoxidase, a green-coloured protein in neutrophil granules. Localized pus accumulation causes an abscess.

ii. Chronic Inflammation:

Chronic inflammation, lasting from weeks to years, may result from unresolved or recurrent acute inflammation; alternatively it may follow exposure to insoluble agents, foreign bodies, intracellular pathogens (e.g. Mycoabacterium tuberculosis or M. Leprae) or unknown aetiological factors, as in rheumatoid arthritis. Whereas the cellular infiltration in actue inflammation consists mainly of neutrophils, in chronic inflammation it is composed of a mixed cell population including macrophages.

The macrophages are derived from blood monocytes which migrate to the site of inflammation, become activated and proliferate. Lymphocytes and plasma cells are usually also present at the sites of chronic inflammation. In some forms of chronic inflammation (e.g. tuberculosis) granulomas are formed.

These consist of collections of epithelioid (epithelial-like) macrophages and lymphocytes, sometimes with much necrotic tissue. Often these necrotic granulomas have the appearance of ‘soft cheese’ and this has led to the alternative designation of ‘caseating granulomas’. The epitheloid macrophages are sometimes very large, with multiple nuclei and are often referred to as giant cells.

Mediators of Inflammatory Reactions:

The inflammatory process is initiated, maintained and controlled by many factors, which often have multiple and interacting effects.

Vasoactive Amines:

The early vasodilation and increased vascular permeability of acute inflammation are caused largely by the release of vasoactive amines such as histamine and 5-hydroxytryptamine (serotonin). These are secreted by a variety of cells including platelets, mast cells and basophils.

Arachidonic Acid Metabolites:

Arachidonic acid metabolites are pro-inflammatory factors which are expressed early, are short-­lived and have a wide range of activities. Prostaglandins cause vasodilation and pain; thromboxanes cause platelet aggregation and vasoconstriction. Leukotrienes increase vascular permeability and leukotriene B4 (LTB4) is a chemotactic and activating factor for leucocytes, especially neutrophils. Chemotaxis is the process by which cells, for example neutrophils are attracted to sites of injury or infection by the release of a specific chemical agent.

Coagulation, Fibrinolytic, Kinin and Complement Systems:

The serous exudate at an inflammatory site contains the components of these systems, which interact and co-activate through a number of initiation stimuli. Thus, activation of Hageman factor (factor XII) of the coagulation system by surface active agents such as damaged connective tissues or microbial components, results in the conversion of fibrinogen to fibrin through the activation of several proteinases including thrombin.

Hageman factor also activates the kinin system, which results in the production of the vasoactive peptide bradykinin from the precursor’s prekallikrein and kininogen. The complement system, like the clotting/fibrinolytic and kinin systems, includes proteolytic enzyme activities in a cascade of events.

Because all these systems rely on the proteolytic activation of latent pro-enzymes (zymogens), there is often cross- activation. In addition, they all contain positive feedback loops which amplify the activation of each system. Complement is activated through the classical pathway by antibodies attached to a target pathogen, or through the alternate pathway by contact with a variety of agents, including bacteria.

The products of complement activation are designed largely to eliminate pathogens and include the following:

1. The release of anaphylatoxins, the small peptides derived from the cleavage of complement factors C3, C4 and C5. These peptides initiate increased blood vessel permeability and smooth muscle contraction, probably by causing histamine release from mast cells. In addition, C5a is a chemotactic factor and an activator of neutrophils.

2. Production of opsonins. Some products of activated complement factors e.g. (C3b) on pathogen surfaces stimulate phagocytosis by effector cells such as neutrophils and macrophages.

3. Lysis of cells by the formation of the lytic or membrane attack complex (MAC) of complement proteins on the target cell membrane.

Cytokines:

Cytokines (including the interleukins, colony-stimulating factors, and tumour necrosis factors) are proteins produced by many cell types. A cell responds to cytokines for which it bears specific surface receptors; the response depends on the concentration of the cytokine and the numbers or ‘affinity status’ of the receptors.

Cytokines modulate a large range of tissue functions, including chemotaxis and activation of inflammatory cells (e.g. leucocytes), morphogenesis, differentiation, proliferation, apoptosis, haemopoiesis and metabolism. Some cytokines activate cell functions directly, Others ‘prime’ cells, making them more sensitive to other stimuli. Cytokines should not be viewed as acting in isolation; cytokines affect cells in cascades or networks.

Leucocyte Recruitment and Activation during Inflammation:

Cell Recruitment:

Changes in blood flow during acute inflammation favour the conditions for the first stage in migration of leucocytes from the blood to the tissues. Cell migration is selective since particular leucocytes are seen in different forms and stages of inflammation. The first stage in migration of blood cells from the blood to the tissue is adherence to the endothelium (margination or pavementing).

Vascular endothelium expresses receptors for adhesion molecules present on the leucocyte surface. The expression of specific receptors on endothelium is induced by the presence of inflammatory mediators.

The process of cell adhesion to endothelium and migration is now recognized as representing an adhesion cascade, which has the following four distinct stages:

1. Tethering:

Tethering, where leucocytes ‘roll’ along the vessel wall, being slowed or ‘tethered’ by low-affinity receptors called selectins; L-selectin is expressed constitutively on leucocytes; E-selectin and P-selectin and expressed on the endothelial cells when activated by cytokines.

2. Triggering:

Triggering involves the induction of adhesion molecules, known as integrins, on the leucocytes following their activation by complement proteins, bacterial products and a variety of cytokines, including platelet-activating factor and interleukin-8 (IL-8).

3. Strong adhesion:

Strong adhesion, where integrins on the leucocytes bind strongly to endothelial cells. Strong adhesion is mediated by activation of the leucocytes and endothelium.

4. Migration:

Migration of the leucocytes through endothelium, a process known as diapedesis. This is mediated by chemotactic factors including – LTB4, bacterial products such as formylated peptides (e.g. frmyl-met-leu-phe), complement peptides, chemokines and soluble peptides derived from damaged connective tissue constituents such as elastin, collagen and laminin. Many chemotactic factors also ‘activate’ leucocyte functions such as phagocytic activity and production of the respiratory burst.

The importance of cell recruitment during inflammation is illustrated by deficiencies such as leucocyte adherence deficiency (LAD), where components of adhesion molecules are absent or reduced, resulting in recurrent infections in the affected individual.

Leucocyte Functions during Inflammation:

Lymphocytes recruited during chronic inflammation contribute to the specific immunological component of pathogen elimination. Neutrophils and macrophages are phagocytic cells, capable of engulfing micro-organisms and, particularly in the case of macrophages, apoptotic or damaged cells and non-living particulate material. Phagocytosis is enhanced if the target is coated by antibodies (opsonized), complement proteins, or both. Phago­cytes have receptors for immunoglobulin (Ig) and complement.

Following their activation phagocytic cells produce a respiratory (oxidative) burst in which the membrane-bound NADPH-oxidase system produces reactive oxygen intermediates such as superoxide radicals (O^–₂), hydrogen peroxide, hypochlorous acid and chloramines. These oxidative products are toxic to micro-organisms.

Individuals with chronic granulomatous disease suffer from recurrent infections because their cells cannot produce these oxidative products. Phagocytosed material is enclosed in a phagocytic vacuole which fuses with lysosomes to form phagolysosomes.

Lysosomes contain proteins and peptides which create ‘holes’ in the membranes of phagocytosed cells, causing lysis, and enzymes which can degrade peptides and proteins, carbohydrates and lipids. Thus there is complete degradation of phagocytosed organic material. Macrophages, eosinophils and mast cells also secrete enzymes and proteins that are damaging to foreign organisms and other cells.

Healing and Tissue Repair of Inflammation:

The main purpose of healing is to replace damaged tissue with functional cells, a process involving migration, proliferation and differentiation of surviving or nearby cells, contraction of the wound by myofibroblasts and production of appropriate connective tissues by cells including fibroblasts and chondrocytes.

Healing begins with the proliferation of fibroblasts and small blood vessels (producing so called granulation tissue). The success of regeneration depends on the type, degree and duration of inflammation and the integrity of remaining tissue.

Some tissues, such as skin and liver, regenerate relatively well whereas others (e.g. nervous tissue) do not. In the absence of regeneration, functional tissue is replaced by fibrotic (scar) tissue composed of large amounts of connective tissue proteins, especially collagen.

The healing process is mediated by a number of hormones, cytokines and growth factors, (including platelet-derived growth factor, epidermal growth factor, and transforming growth factors α and β) which interact in complex networks. They can act in synergy and some are inhibitory.

The resolution of the inflammatory process depends on the removal of the initial insult and changes in the pattern of mediators from those which are pro-inflammatory to those which induce healing. Remaining inflammatory cells appear to undergo apoptosis and are recognized and phagocytosed by macrophages.