Inflammation is a fundamental biological process designed to protect the body against injury, infection, or tissue damage. It represents a rapid, coordinated response by the immune and vascular systems to eliminate the initial cause of cell injury and initiate repair. The pathophysiology of inflammation occurs when this beneficial defense mechanism becomes dysregulated, persisting beyond its protective role to actively contribute to disease and tissue destruction. This shift from a temporary response to a sustained, harmful process is central to understanding chronic diseases.
Acute Inflammation: The Immediate Cellular Response
The initial inflammatory event is triggered by resident tissue cells, such as mast cells and macrophages, which sense foreign molecules from pathogens or damage-associated molecules released from injured host cells. These cells use specialized pattern recognition receptors to detect the threat, quickly launching the acute response. Local blood vessels immediately undergo changes to increase blood flow and permeability, resulting in the classic signs of heat and swelling at the injury site.
Chemical mediators are immediately released to orchestrate the vascular changes. Histamine, released by mast cells, causes vasodilation and increased blood flow. This increased flow delivers immune cells and plasma proteins to the affected area, while molecules like prostaglandins increase pain sensitivity. Increased vascular permeability allows fluid and plasma proteins to leak into the tissue space, creating swelling, or edema.
The most characteristic event of acute inflammation is the recruitment of immune cells, primarily neutrophils, from the bloodstream to the site of injury, a process known as extravasation. This migration occurs sequentially, beginning with a loose interaction between circulating white blood cells and the vessel wall. Weak bonds form between selectin molecules on the vessel lining and ligands on the neutrophil surface, causing the cell to “roll” along the endothelium.
Chemokines then activate integrin molecules on the rolling neutrophils, leading to “firm adhesion” that arrests movement. Finally, the neutrophil uses adhesion molecules to squeeze between endothelial cells and exit the vessel (transmigration or diapedesis). Once in the tissue, neutrophils follow the chemokine gradient (chemotaxis) directly to the injury source to engulf and destroy the offending agents.
The Transition to Resolution or Persistent Inflammation
A healthy acute inflammatory response is self-limiting and must be actively terminated to prevent unnecessary tissue damage. The transition to resolution is a tightly controlled biochemical program that begins immediately after the threat is neutralized. This involves switching from the production of pro-inflammatory mediators to specialized pro-resolving mediators (SPMs).
These SPMs are derived from omega-3 fatty acids and include molecules like resolvins and lipoxins. Resolvins signal existing neutrophils to stop entering the tissue and undergo programmed cell death (apoptosis). Lipoxins block the action of pro-inflammatory molecules, effectively halting the cascade.
Resolution requires the efficient clearance of cellular debris, including apoptotic neutrophils. Macrophages, which arrive later than neutrophils, engulf these dying cells and any remaining pathogens, a process known as efferocytosis. After clearing the site, macrophages shift their phenotype from pro-inflammatory to pro-resolving, producing anti-inflammatory cytokines that promote tissue healing.
Pathophysiology occurs when this resolution program fails, often because the inciting agent, such as a persistent infection or an autoimmune trigger, cannot be cleared. The continued presence of the stimulus, or a defect in generating SPMs, maintains the pro-inflammatory signaling. This failure of resolution leads to chronic inflammation, where the temporary protective response spirals into a prolonged state of tissue injury.
Chronic Inflammation: Sustained Tissue Damage
When inflammation persists for weeks, months, or years, it is characterized by a shift in the dominant cell types present. Short-lived neutrophils are replaced by long-lived immune cells, primarily macrophages, lymphocytes (T and B cells), and plasma cells. These cells form the foundation of a sustained immune reaction.
Persistent macrophages and lymphocytes continuously secrete potent inflammatory mediators, including interleukins and tumor necrosis factor-alpha (TNF-α). This chemical signaling creates a self-perpetuating cycle of damage and attempted repair. Chronic inflammation involves simultaneous tissue destruction and healing, leading to a profound alteration of the tissue architecture.
A major destructive mechanism is the sustained release of reactive oxygen species (ROS) and various enzymes by active immune cells. While intended to destroy pathogens, constant release causes oxidative stress that damages surrounding healthy cells and their DNA. This injury perpetuates inflammatory signaling, creating a vicious cycle that prevents the tissue from fully healing.
Tissue remodeling and fibrosis are the most significant long-term structural consequences of chronic inflammation. Fibroblasts, which lay down connective tissue, are perpetually activated by pro-fibrotic cytokines like Transforming Growth Factor-beta (TGF-β1) secreted by macrophages. This activation causes fibroblasts to transform into myofibroblasts, which overproduce extracellular matrix components, notably collagen. The resulting excessive accumulation of connective tissue (fibrosis or scarring) replaces functional tissue, leading to organ stiffness and malfunction.