Acute Inflammation

Overview
  • Acute Inflammation is a general pattern of immune response to Cell Injury characterized by rapid accumulation of immune cells at the site of injury. The acute inflammatory response is initiated by both immune and parenchymal cells at the site of injury and is coordinated by a wide variety of soluble mediators.
Cellular Pathogenesis
  • Overview
    • The pathogenesis of acute inflammation occurs progressively through several stages of prominent cellular changes. Initially, vasculature within and around the site of injury responds by increasing blood flow and enhancing vascular permeability. Subsequently, immune cells are recruitment to the vasculature and extravasate into the injured parenchyma. Extravasated immune cells then migrate to the injured cells using gradients of inflammatory molecules as a guide, termed chemotaxis. Once immune cells reach the site of injury they proceed to phagocytose and degrade cellular debris and any microbes which may be present.
  • Vascular Changes
    • Immediately following the injurious stimulus there is a brief period of arteriolar vasoconstriction for several seconds followed by a sustained vasodilation of local arterioles allowing for substantially increased blood flow to the injured area. Additionally, endothelial cells in local capillary beds contract, generating spaces between the cells which substantially increase vascular permeability. In some injurious scenarios, such as burns, increased vascular permeability may be a result of direct damage to endothelial cells. Increased local blood flow accounts for the clinically visible heat and redness associated with acute inflammation while the increased vascular permeability accounts for the localized edema.
  • Immune Cell Extravasation
    • Following the initiation of vascular changes, a variety of leukocytes bind to involved blood vessels and exit into the parenchyma. However, the primary immune cell type to do so in settings of acute inflammation is the neutrophil. Binding and extravasation of leukocytes follows a series of well-described stages.
    • Margination: The vasodilation described above generally slows the flow of blood at the site of injury and causes immune cells to move toward the periphery of the vessel, next to the vascular wall.
    • Rolling: Marginated immune cells initially display transient, low affinity interactions with endothelial cells which result in their slowing down and literal rolling along the vascular wall. These interactions are mediated by Selectins.
    • Adhesion: Rolling sufficiently slows the immune cells to allow for much higher affinity interactions between leukocyte Integrins and endothelial ICAMs to take place. These interactions strongly adhere the cells to the vascular wall, stopping their further travel through the blood stream.
    • Extravasation: Once bound to the vascular wall immune cells extravasate into the parenchyma by squeezing between endothelial cells. Interestingly, transmigrating leukocytes must dissolve the underlying basement membrane using a variety of proteases
  • Chemotaxis
    • Newly extravasated leukocytes migrate to the site of injury along gradients of soluble chemical mediators (Chemotactic factors). Some of these chemotactic factors are secreted by host cells at or near the site of injury while others may be shed microbial components.
  • Phagocytosis
    • Upon arrival at the site of injury, immune cells begin to phagocytose and degrade cellular debris along with any present microbes. Ultimately, clearance of injured host cells and removal of microbes is the prime goal of the entire inflammatory process. However, some recruited immune cells such as Macrophages and Dendritic Cells additionally travel to local lymph nodes with degraded phagocytosed debris and act as Antigen Presenting Cells, thus initiating a potential Adaptive Immune Response to a microbe, if present.
Molecular Pathogenesis
  • Overview
    • A large variety of soluble molecules allow coordination of the complex cellular events described above. A detailed description of each of these molecules is far beyond the scope of an introductory medical text. Below we highlight several classes of soluble mediators and briefly point to their role in acute inflammation. In general, mediators are either synthesized by cells at the site of injury or derived by activation of circulating precursors. Most act locally to promote the cellular events described above although some act systemically to modify a variety of processes including host metabolism, psychological behavior, and Hematopoiesis, thus generating a systemic state of illness. Additionally, many inflammatory mediators modulate the synthesis of others, allowing for significant cross-regulation and fine-tuning of the inflammatory response.
  • Vasoactive Amines
    • Histamine: Released from Basophils, Mast Cells, and platelets. Increases vascular permeability
    • Serotonin: Released from platelets. Increases vascular permeability
  • Inflammatory Lipids
    • Inflammatory lipids are synthesized from plasma membrane lipids and are produced by a variety of immune and parenchymal cells at sites of inflammation. Most are metabolites of Arachidonic Acid, with the exception of Platelet Activating Factor (PAF). Some lipids promote inflammation whereas others are clearly regulatory and serve to limit excessive inflammation.
    • Vasoconstriction: Thromboxane A2, LTC4, LTD4, LTE4
    • Vasodilation: PGI2, PGE1, PGE2, PGD2, Lipoxins
    • Increase Vascular Permeability: LTC4, LTD4, LTE4, PAF
    • Increase Chemotaxis: Lipoxins, 5-HETE, PAF
    • Decrease Chemotaxis: LTB4
    • Increased Platelet Aggregation: Thromboxane A2, PAF
    • Decreased Platelet Aggregation: PGI2
  • Complement
    • The activation of complement is described in further detail in its own page (See: Complement). Specifically in relation to acute inflammation, activation of the Complement cascade promotes several processes. C3a and C5a induce degranulation of mast cells and basophils which releases histamine and thus causes vasodilation and increased vascular permeability. C5a can also promote the generation of several inflammatory lipids and induces chemotaxis of immune cells. Additionally, opsonization of microbes by C3b promotes their phagocytosis.
  • Cytokines
    • Cytokines are soluble proteins secreted by both immune and parenchymal cells which can act in a both autocrine and paracrine manner to change cellular behavior to either promote or inhibit inflammation. Cytokines play a wide variety of roles in immunity and here we discuss only those critical for acute inflammation. TNF-alpha and IL-1 are secreted by both immune and parenchymal cells at sites of inflammation and can promote immune cell extravasation by activating endothelial cells to express adhesion molecules for immune cells. TNF-alpha and IL-1 in some sense are master regulatory of inflammation as they induce the expression of many other inflammatory cytokines and chemokines. IL-8 is produced at sites of inflammation and promotes neutrophil chemotaxis to the site of injury.
  • Nitric Oxide
    • Nitric Oxide plays a wide variety of roles in different organs. In terms of inflammation, Nitric Oxide can be inducibly synthesized in activated immune cells by inducible-Nitric Oxide Synthase (iNOS). The synthesized Nitric Oxide can be used to kill phagocytosed bacteria but also diffuses locally to inhibit excessive inflammation. It appears that locally diffusing Nitric Oxide can reduce leukocyte recruitment to sites of injury and reduce Platelet Aggregation:.
  • Coagulation Cascade
    • Activation of the coagulation cascade produces soluble mediators which can promote inflammation.
    • Thrombin: Increases endothelial selectin expression which enhances leukocyte recruitment
    • Fibrinopeptides: Are breakdown products of fibrin. Increase vascular permeability and can act as chemotactic agents
    • Bradykinin: Increases vascular permeability, causes vasodilation, and induces the sensation of pain associated with acute inflammation
  • Microbial Products
    • Several products shed from bacteria can potently promote inflammation. As explained in the Innate Immune Response, immune and parenchymal cells possess microbial Pattern Recognition Receptors which bind molecular constituents of microbes and are the stimulated to release a large variety of soluble inflammatory mediators. Additionally, N-formylated peptides, which are only produced by bacteria, can act as chemotactic factors for neutrophils.
Clinical Consequences
  • Acute inflammation is traditionally characterized by a number of gross, clinically identifiable features:.
  • Calor: Heat (Due to increased blood flow)
  • Rubor: Redness (Due to dilation of blood vessels)
  • Tumor: Swelling, formally a localized edema (Due to increased permeability of vessels and resultant extravasation of protein-rich fluid)
  • Dolor: Pain (Due to chemical mediators such as bradykinin)
  • Functio laesa: Loss of function
Sequelae
  • Overview
    • Acute Inflammation is generally considered a process which lasts several days. Following this time period several outcomes may result as described below.
  • Resolution
    • This is the most favorable outcome and is characterized by clearance of injured cells along with any microbes followed by restoration of the normal tissue architecture. Resolution occurs when the source of injury is transient and cellular damage is minimal. Extravasated immune cells are removed with different modalities: Neutrophils undergo apoptosis while macrophages and other cells travel out of the tissue via lymphatic vessels.
  • Abscess formation
    • When the source of injury is concentrated and intense, large numbers of neutrophils may be recruited to the site of injury. Neutrophils often release potent degradative enzymes into the surrounding tissue which can severely damage host cells and result in significant destruction of tissue architecture. The combination of recruited neutrophils which rapidly undergo apoptosis together with damaged cellular debris and any present microbes manifests as an Abscess.
  • Chronic Inflammation
    • In many cases the processes of acute inflammation are not sufficient to remove the source of injury. Additionally, the inflammatory processes themselves may initiate further injury which induces further inflammation, thus causing a self-perpetuating inflammatory loop. Such scenarios where inflammation lasts longer than several days are termed Chronic Inflammation (see page). When acute inflammation transitions into chronic inflammation the histomorphological pattern transitions as described further in Chronic Inflammation.
Morphology
  • In general, acute inflammation is characterized by the presence of large numbers of neutrophils although other leukocytes are recruited as well. Consequently, when you encounter histopathological descriptions which primarily cite the presence of neutrophils over and above other types of immune cells, consider this an indication that an acute inflammatory process is at work.