Chronic inflammation is inflammation which has been of prolonged duration. It is the simultaneous occurrence of active inflammation, tissue destruction and attempts at repair.
Chronic inflammation can either follow on from acute inflammation or it can begin insidiously (a lack of symptoms, the patient is unaware of the onset of the disease with a subtle and cumulative harmfulness) e.g. tuberculosis. If you have persistent symptoms listed below, it is best to contact your doctor and you should stop going to a casino where a lot of people you can intervene, perhaps you should stay at home and Play DaisySlots for a while. There should not be a big difference between land-based and online casinos.
Chronic inflammation arises with the following conditions:
- Persistent infections such as those from mycobacteria or certain fungi/parasites. This may cause type IV hypersensitity (delayed-type) but has low toxicity. This is a granulomatous inflammation
- Prolonged exposure to exogenous or endogenous (potentially toxic) agents
- Autoimmunity where auto-antigens evoke a self-perpetuating immune reaction which results in chronic inflammation
The histological features of chronic inflammation:
- Tissue section infiltrated with mononuclear cells (macrophages, lymphocytes, plasma cells)
- There is tissue destruction which has been mainly induced by inflammatory cells
- There are attempts at repair of this tissue, characterised by; connective tissue replacing the damaged tissue, proliferation of small blood vessels (angiogenesis – formation of new blood vessels) and fibrosis
Macrophages are the most important leukocyte in chronic inflammation. When the macrophages are inactivated they are monocytes in the blood vessels. A monocyte in a vessel has a half-life of approximately 1 day, however the differentiation and activation of the monocyte, forming a macrophage as it moves into tissue allows it to survive for several months.
Monocytes begin to emigrate relatively early on in acute inflammation and become the predominant cell type within 48 hours.
The persistent accumulation of macrophages in chronic inflammation is due to:
- The continued recruitment of monocytes from the blood circulation (This is due to the continual expression of adhesion molecules and chemotactic factors such as C5a, chemokines, etc.)
- The local proliferation of macrophages
- Immobilisation of macrophages (e.g. by chemokines such as macrophage inhibitory factor and oxidised lipids)
Comparison of Neutrophils and Macrophages:
- Terminally differentiated when arriving at site of injury
- Monocytes differentiate into tissue macrophages which are activated by inflammatory stimuli
- Incapable of cell division
- Mitotically active
- Execute limited stereotypic mission (extravasation, chemotaxis, phagocytosis, degranulation)
- Do what do neutrophils as well as mediate systemic effects (fever, leucocytosis, acute phase response)
Other cells involved with chronic inflammation:
- Lymphocytes – They have a reciprocal relationship with macrophages, when a lymphocyte comes into contact with an antigen, it releases cytokines which activate macrophages. Macrophages also release cytokines which further activate lymphocytes
- Plasma cells – Ig-producing differentiated B cells (Russell bodies are plasma cells who have a dilated golgi body full of Ig so they appear larger and darker coloured)
- Mast cells – Secrete cytokines leading to recruitment of further leukocytes (parasitic infections)
- Eosinophils – Release major basic protein which is toxic to parasites
- Neutrophils – Occur in chronic suppurative inflammation (purulent – pus inflammation)
This is induced mainly by the inflammatory cells, in a process called Leukocyte-induced tissue injury. Tissue destruction occurs due to the presence of lysosomal enzymes; oxygen derived active metabolites and the formation of products from arachidonic acid metabolism (prostaglandins, leukotrienes etc.)
Attempts at Healing/Repair
Healing is the replacement of dead/damaged or removed tissue with healthy tissue in an attempt to restore anatomical and functional integrity. This occurs by one of two processes, either regeneration or repair. This involves cell migration, cell proliferation, cell differentiation and cell matrix interactions.
Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction. The predominant cell type is the activated macrophage however it has modified epithelial like (epithelioid) appearance. Mycobacteria are the agent responsible for granuloma formation.
A granuloma is the focal area of a granulomatous inflammation, it is a ball-like collection of immune cells which forms when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Older granumlomas develop an enclosing rim of fibroblasts and connective tissue; multinucleate giant cells may also be present.
There are two type of granulomas inflammation:
- Foreign body Granuloma – This type of granulomatous inflammation is induced by relatively inert foreign bodies which are too big to be phagocytosed by a single macrophage. They have not induced an inflammatory/immune response. (Epithelioid cells and giant cells are located next to the surface and encircle the foreign body – this isn’t visible in histology slides)
- Immune Granuloma – This type of granuloma is induced by insoluble particles which invoke a cell-mediated immunity response. Macrophages engulf, process and present the foreign material (this activates T-cells leading to the production of IL-2 which activates further T-cells)
- Granulomatous inflammation – A macrophage dominated chronic inflammation
- Granuloma – The focal point of a granulomatous inflammation. The centre will contain macrophages and epithelioid cells whilst the periphery will contain lymphocytes and plasma cells (Plus in older cells there will be a rim of fibroblasts and connective tissue)
- Granulation tissue – Ingrowth of new blood vessels into deposited fibrin during repair (Granular surface)
- Granulocytes – Lymphocytes which have a granular appearance and contain granules (Neutrophil, eosinophil and basophil)
Morphological Patterns of Chronic Inflammation
Chronic Proliferative Inflammation
The formation of granulation tissue occurs; chronic recurring inflammation is the chronic proliferation inflammation with acute bouts which entails the recruitment of additional neutrophils.
An abscess is suppurative inflammation which is buried deep within a tissue, organ or other confined space.
Abscess are formed by bacteria with a lower amount of hyaluronidase enzyme which means they spread slower but induce a strong local reaction
Necrosis of tissue occurs due to bacterial toxins and reduced perfusion; neutrophils emigrate towards the area and phagocytose the bacteria. Necrosis results in the liquefaction of the abscess (early phase of abscessation)
Composition of an abscess:
- Inner layer – Purulent exudate
- Middle layer – Young, cell rich granulation tissue
- Outer layer – Older, cell poor, fibre rich granulation tissue
The outcome of the composition of an abscess results in the walling off of the abscess or perforation
An ulcer is a local defect or excavation on the surface of an organ/tissue that is produced by the sloughing (shedding) of inflammatory necrotic tissue. This can only occur with the presence of an inflammatory necrotic area on or near the surface. This occurs most commonly in:
- Oral cavity
- Urogenital tract
At the acute stage of an ulcer (early on) there is intense neutrophilic inflammation and vascular dilations at the margins of defect.
During the chronic stage of the ulcer there is fibroblastic proliferation at the margins (resulting in wall formation) and base of the defect. There is also scarring and the accumulation of mononuclear cells.
As described earlier, the healing process can either be regenerative (the formation and development of new tissue with full function and no scarring e.g. the renewing of the epidermis) or repairing (the healing of wounds and chronic inflammation resulting in scarring and fibrosis). Visit this website for effective ways to reduce inflammation.
Repair by Connective Tissue (Fibrosis)
This occurs in when healing is required where full healing cannot be accomplished from parenchymal cell regeneration alone, even in organs where the cells are able to regenerate. Attempts to repair the damage are made by replacing the non-regenerated parenchymal cells by connective tissue, this is called fibrosis and it leads to scarring.
Repair begins early in inflammation (roughly 24 hours after injury) and if a resolution to the inflammation has not occurred by 3-5 days later fibroblasts and vascular endothelial cells proliferate to form granulation tissue (This contains new small blood vessels and proliferating fibroblasts – new vessels leak and so the tissue is oedematous).
There are four components to fibrosis, these are:
- Migration and proliferation of fibroblasts
- Extracellular matrix deposition
- Remodelling of fibrous tissue
Angiogenesis is neovascularisation (neo – new, vascularisation – blood vessels, the forming of new blood vessels). Angiogenesis works by causing local pre-existing vessels to send out capillary buds/sprouts to produce new vessels. This is critical in chronic inflammation and fibrosis.
This can be described in four steps:
- Proteolytic degradation of the basement membrane of the parent vessel
- Migration of endothelial cells towards the angiogenic stimulus
- Proliferation of the endothelial cells and remodelling into capillary tubes
- The recruitment of periendothelial cells, this includes cells such as pericytes (small vessels) and smooth muscle cells (for larger vessels). Their function is to support the endothelial tubes.
The angiogenic stimulus is called VEGF (vascular endothelial growth factor), its secretion is stimulated by TGF (transforming growth factor), PDGF (platelet derived endothelial growth factor), TNF (tumour necrosis factor) or tissue hypoxia.
Migration and Proliferation of Fibroblasts
VEGF is not only associated with the promotion of angiogenesis, it also creates a marked increase in vascular permeability. This leads to an increased deposition of plasma proteins (fibrinogen, fibronectin) in the extracellular matrix. It also provides provisional stroma for fibroblast (and endothelial cell) ingrowth.
The migration and subsequent proliferation of fibroblasts is triggered by growth factors and fibrogenic cytokines. The sources of these are platelets, inflammatory cells (macrophages) and the activated endothelium.
Extracellular Matrix Deposition
Fibroblasts are now increasing the amount of extracellular matrix being synthesised and secreted. (This secretion includes fibrillar and non fibrillar collagens). This is important for the development of strength in a healing wound.
Collagen synthesis by fibroblasts begins as early as 3-5 days after initial inflammatory response and it can continue for several weeks depending on the size of the wound.
The secretion of extracellular matrix collagen components is stimulated by growth factors and cytokines which are secreted by leukocytes and fibroblasts.
A scar is the ultimate outcome of granulation tissue; a scar is composed of spindle-shaped fibroblast, dense collagen, fragments of elastic tissue and other extracellular components. With mature scars, vascular regression occurs which leads to the scar becoming avascular.
Tissue remodelling is the replacing of the granulation tissue with a scar; this process involves alterations in the composition of the extracellular matrix. Degradation of the collagen and other extracellular matrix proteins is mediated by matrix metalloproteinases (MMP’s) which are zinc dependent.
- Interstitial collagenases cleave the fibrillar collagens I, II and III
- Gelatinases (type IV collagenases) degrade amorphous collagen and fibronectin
- Stromelysins degrade proteoglycans, laminin, fibronectin, amorphous collagen
- Elasteases degrade elastin
Production of MMP’s occurs in fibroblasts, macrophages, neutrophils, synovial cells and some epithelial cells. Their secretion is induced by PDGF, FGF, IL-1, TNF and phagocytosis, their secretion is inhibited by TGF and steroids as well as tissue inhibitors of MMP’s (known as TIMP’s). TIMP’s are produced by most mesenchymal cells and their function is to prevent the uncontrolled action of MMP’s
The healing of wounds involves the following components:
- Initially, there is induction of the acute inflammatory process caused by the primary injurious agent
- Regeneration of parenchymal cells
- The migration and proliferation of parenchymal cells and connective tissue cells
- The synthesis of extracellular matrix products
- Remodelling of connective tissue and parenchymal components
- Collagenisation and acquisition of wound strength
These processes are achieved by:
- Mediators of acute inflammation
- Growth factors
- The interactions between cells and the extracellular matrix
- Angiogenesis and fibrosis
Healing by First Intention
Healing by first intention is the healing of wounds with opposing sides, for example clean incisions made by a surgical scalpel. This type of wound results in the death of a limited number of epithelial and connective tissue cells as well as disruption of the epithelial basement membrane continuity.
The cavity caused by the incision in this type of wound is filled immediately with clotted blood which contains both fibrin and blood cells. The dehydration of this clot on the surface is what forms scabs.
- Neutrophils appear at the margin of the incision, they move towards the fibrin clot
- The epidermis thickens at the cut edges, this is due to the mitotic activity of the basal cells
- Bursts of epithelial cells from the edges migrate and grow along the cut margins of the dermis and deposit basement membrane components as they move
- Macrophages have become the dominant leukocyte type, replacing neutrophils
- Granulation tissue progressively encroaches on the incision space
- Collagen fibres become present in the margins of the incision (However, they do not bridge the incision as that would require horizontal orientation, these collagen fibres are vertically orientated).
- There is continuation of epithelial proliferation resulting in the thickening of the epithelial covering layer
- The incision space is now filled with granulation tissue
- Neovascularisation (formation of new vascular architecture) is at a maximal rate
- Collagen fibres are becoming more abundant and begin to bridge the incision
- The epidermis recovers to its normal thickness, surface cells become differentiated and a mature epidermal architecture forms
- There is continued accumulation of collagen and proliferation of fibroblasts
- Any leukocytic infiltrate, oedemas or increased vascularity have been reduced greatly or disappeared
- Blanching begins – this is the increased accumulation of collagen, which is accompanied by the regression of vascular channels
- A scar has formed, comprising of a cellular connective tissue which is devoid of any inflammatory cells. This scar tissue is covered by an intact epidermis
- There is a permanent loss of dermal appendages which were destroyed with the incision, these appendages are unable to regenerate
- A gradual increase in tensile strength which continues for months after initial injury
Healing by Second Intention
Wounds repaired by second intention are those with largely separated edges, therefore the reparative processes are more complicated due to the extensive loss of cells and tissue. These types of wounds arise from infarction, ulceration, abscesses and surface wounds which have created a large defect.
In these cases where there has been a lot of damage to tissue, the defect which is left has to be filled. However because parenchymal cells can’t completely reform the original architecture an abundance of granulation tissue grows in from the margin to complete the repair. This process differs from primary healing by:
- A more intense inflammatory reaction – this is due to the higher amount of fibrin and necrotic tissue debris and exudate
- The formation of larger amounts of granulation tissue
- Wound contraction which only occurs in large surface wounds
After 1 week of injury, the tissue structure is fairly weak at only 10% of its original strength, over the next 4 weeks there is a rapid increase in strength which slows down again by 3 months. At this time tissue strength is at 70-80% of its original.
The increase in tissue strength is due to the synthesis of collagen being greater than the degradation of collagen, this being the case for approximately 2 months. The collagen fibres are also modified to increase in strength and size by forming cross-links
Factors Influencing Wound Healing
Factors affecting the efficiency of wound healing can either be systemic or local:
- Nutrition – a deficiency in protein and/or vitamin C can reduce collagen synthesis meaning slower wound healing
- Anti-inflammatory hormones such as glucocorticoids can reduce collagen synthesis
- Bacterial infection
- Mechanical action can inhibit healing
- Foreign material can slow down healing
- Size and location of wound, smaller well vascularised wounds heal faster.
Pathologic Aspects of Wound Healing
This could be that scar formation is deficient, which would result in wound dehiscence (the rupture of the wound due to mechanical stresses) or ulceration, which would be due to inadequate vascularisation or areas devoid of sensation.
Another possibility is that there is excessive formation of the repair components e.g. excess collagen; this would result in a keloid, hypertrophic scar. Or excess amounts of granulation tissue; this would block any attempt at re-epithelialisation due to protrusion contracture.
Finally there could be exaggerated contraction; this would result in the deformation of the tissue.
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