Inflammation

Inflammation is a key component of some forms of arthritis, particularly rheumatoid arthritis. It serves as both a response to tissue injury and a mechanism for the initiation of tissue repair. Although the inflammatory process may facilitate repair with little
damage to normal tissues, it can also be associated with significant tissue destruction.

The cardinal signs of inflammation are rubor (redness), calor (heat or warmth), tumor (swelling), dolor (pain), and functio laesa (loss of function).

Inflammatory responses occur in three distinct phases:

• An acute transient phase, characterized by local vasodilation and increased capillary permeability
• A delayed phase, characterized by the infiltration of white blood cells and phagocytic cells
• A chronic proliferative phase, in which tissue degeneration and fibrosis occur

During the first phase of inflammation, plasma and white blood cells move out of capillaries through gaps in the capillary walls and begin to accumulate in the tissues. The heat, redness, and swelling characteristic of inflammation occur as a result of this vascular response In synovial tissue, this first phase of inflammation is followed by a second phase in which there is an increase in the number and size of synovial lining cells and edema  of the synovial membrane. This increases the thickness of the membrane, resulting in the development of multiple folds and villi  on the membrane surface. New blood vessels grow, providing a route for the delivery of white blood cells and fluid. In addition, T-lymphocytes, B-lymphocytes, and macrophages migrate into the synovial membrane and proliferate during the second phase of inflammation. These cells elaborate a number of proinflammatory cytokines. In addition, B-lymphocytes differentiate into antibodyproducing plasma cells, and polymorphonucleocytes accumulate in the synovial fluid. Among the chemical mediators produced by lymphocytes and
macrophages are interleukin-1 (IL-1) and tumor necrosis factor-alpha.

These cytokines play important roles in:

• Synovial tissue and fluid inflammation
• The proliferation of synovial membrane cells
• The production of cartilage and bone damage
• Systemic symptoms of disease

Following exposure to IL-1 and TNF-, inflammatory mediators, such as nitric oxide (NO), may be formed by chondrocytes in the articular cartilage or by cells in the synovial membrane. Nitric oxide can cause the degradation of the extracellular matrix of joint tissues, affect cell proliferation and survival, and modulate the production of other pro-inflammatory mediators. Two other important mediators produced in inflamed joints are prostaglandins and leukotrienes. These substances accentuate the signs and symptoms of inflammation by potentiating vasodilation and vascular permeability and by sensitizing nerve endings to osteoarthritis pain signals generated in the joints. Both IL-1 and nitric oxide enhance the production of inflammatory prostaglandins.