CHRONIC INFLAMMATION

Chronic inflammation is inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction and attempts at healing are proceeding simultaneously. Such inflammation arises under the following settings:

1. Persistent infection by certain microorganisms such as tubercle bacilli, Treponema pallidum. These organism are of low toxicity and evoke an immune reaction called delayed hypersensitivity. The inflammatory response takes a specific pattern called a granulomatous reaction. 2. Prolong exposure to potentially toxic agents either exogenous or endogenous; e.g Silicosis and atherosclerosis.

3. Under certain conditions, immune reactions are set up against the individuals own tissues leading to autoimmune disease such as Rheumatoid arthritis, lupus erythematosus.

Chronic inflammation is characterized: Infiltration with mononuclear cells, include macrophage, lymphocytes and plasma cells, a reflection of persistent reaction to injury

2. Tissue destruction induced by the inflammatory cells 3. Attempts at repair by connective tissue replacement namely proliferation of small blood vessels (angiogenesis) and in particular fibrosis.

Mononuclear Infiltration
Macrophages are one component of mononuclear phagocyte system (MPS) previously known as the reticulo endothelial system (RES). MPS related with cells of bone marrow origin, including blood monocytes and tissue macrophages.

Macrophages are diffuse scatter in the connective tissue or cluster in organ such as Kupffers cell. (in liver, sinus histiocytes in spleen and lymph node) and alveolar macrophage (in lung) From the blood monocytes migrate into various tissue and transform into macrophage. The half life of blood monocyte is about one day, where life span of tissue macrophage is several months

To performing phagocytosis, macrophages have the potential of being activated a process that result in a increase in cell size, increased level of lysosomal enzymes, more active metabolism, and more ability to phagocytes and kill ingested microbes. Activation signals include cytokine (Interferon gamma = IFN ) secreted by sensitized T lymphocytes, bacterial endotoxins, other chemical mediators, ECM protein lie fibronectin.

In short lived acute inflammation, if the irritant is eliminated, macrophages eventually disappear (either dying off or making their way into the lymphatic or lymph node) Three mechanisms for macrophages accumulation: 1. The most important is continued recruitment of monocyte from the microcirculation, which results from the steady expression of adhesion molecules and chemotactic factor.

Chemotactic stimuli for monocytes include C5a, cytokine of the IL-8 family produced by activated macrophages and lymphocytes (eg MCP-1 for monocytes) certain growth factor such as PDGF and TGF (beta) fragments from breakdown of collagen and fibronectin and fibropeptides 2. Local proliferation of macrophages after their emigration from the blood stream 3. Immobilization of macrophage within the site of inflammation (certain cytokines macrophage inhibitor factor) and oxidized lipids can cause immobilization

Other types of cells present in chronic inflammation are lymphocytes, plasma cells, eosinophils and mast cell. Lymphocyte are mobilized in both antibody and cell mediated immune reaction and also for reason unknown, in non immune mediated inflammation. Lymphocytes of different types (T and B) use various adhesion molecules (VLA-4/VCAM-1 and ICAM-1/ LFA-1 predominantly) and chemical mediator/ cytokines to migrate into inflammatory sites.

Lymphocytes can be activated by contact with antigen. Activated lymphocyte produce lymphokines and one of these, IFN is a mayor stimulator of monocytes macrophages. Cytokine from activated macrophages (monokine) in turn activate lymphocyte. Plasma cells produce antibody directed either against persistent antigen in inflammatory site or against altered tissue components.

Eosinophils are characterized of immune reaction mediated by Ig E and of parasitic infection. Like neutrophils they use adhesion molecules and chemotactic agents derived from mast cells, lymphocytes or macrophages) to exit the blood. Eosinophils are phagocytic and undergo activation. Their granules contain major basic protein (MBP) a highly cationic protein that is toxic to parasites but also causes lysis of mammalian epithelial cells

Although neutrophils are the hallmark of acute inflammation, many forms of chronic inflammation, lasting for months continue to show large number of neutrophils, induced either by the persistent bacteria or by mediators produced by macrophages or necrotic cells. In chronic bacterial inflammation of bone (osteomyelitis) a neutrophils exudate can persists for many months

Repair by Connective Tissue (fibrosis)

Persistent tissue destruction, with damage to both parenchymal cells and stromal framework is a hallmark of chronic inflammation. There are four components to this process: 1. Formation of new blood vessels (angiogenesis) 2. Migration and proliferation of fibroblast 3. Deposition of extracelullar matrix 4. Maturation and organization of the fibrous tissue also known as remodeling

The hallmark of healing can find the granulation tissue (3-5 days) fibroblast and vascular endothelial cells being proliferating to form the specialized type of tissue. The term granulation tissue derives from its pink, soft, granular appearance on the surface wounds and the histologic features that are characteristic: the proliferation of new small bood vessels and fibroblasts. Angiogenesis is an important biologic process in repair and also involve in progresive growth of cancer.

The new granulation tissue is often edematous Several factors can induce angiogenesis, notably basic FGF, VEGF, Vascular Permeability Factors (VPF). Basic FGF can mediate all the steps angiogenesis, both in vivo and in vitro and increased vascular permeability, is an excellent candidate for tumor angiogenesis and for blood growth in normal development and also be involved in chronic inflammation and wound healing.