Notes
Acute Inflammation - Essentials
Sections
Overview
The acute inflammatory response is activated in the presence of infectious agents and/or damaged tissues.
Acute inflammation triggers vascular and cellular responses that deliver cells and proteins to the site of cell injury.
Key steps of this process include:
– Recognition of inflammatory agents.
– Leukocyte and plasma protein recruitment from the blood to the tissues.
– Leukocyte activation.
– Control and termination of inflammatory reactions, which are otherwise harmful to healthy cells.
Recognition of offending agents
Microbes
Cellular receptors for microbes exist in the plasma membranes, endosomes, and cytosol of host cells.
For example: Toll-like receptors (TLR) enable dendritic and other "sentinel cells" to recognize invading microbes.
Host cell damage
Cytosolic sensors recognize various molecules, such as uric acid, ATP, DNA, and reduction of intracellular potassium concentrations, that indicate cellular damage.
For example: Multi-protein cytosolic complexes called inflammasomes respond to the cytosolic sensors and trigger the release of cytokines, which, as we'll see, are key mediators of the inflammatory response.
Plasma Protein and Leukocyte Recruitment
Recruitment of plasma proteins and leukocytes from the blood
Vasodilation and increased permeability of the vessel wall:
Triggered by inflammatory mediators, importantly: histamine, prostaglandins, platelet activating factor (PAF), thromboxane A2 (generated from prostaglandins).
Plasma proteins and fluid exit the vessel
Aka, exudation.
This process can lead to excess fluids in the interstitial tissues, a condition called "edema."
Neutrophil recruitment from the blood involves:
Capture, Rolling, Adhesion, Diapedesis, and Chemotaxic Migration.
Capture:
Capture pulls neutrophil from blood stream and loosely adheres them to the vessel wall.
Rolling:
Neutrophils roll along vessel wall.
Adhesion:
Firmer adhesion in preparation for exit.
Diapedesis:
The process of movement across the vessel wall typically occurs via the paracellular route.
Once outside of the vessel, neutrophils generate more cytokines, which further promotes the inflammatory response.
Migration:
Chemokines guide neutrophils to the site of inflammation along chemotactic gradients.
Phagocytosis and destruction of inflammatory agents
Phagocytosis
We'll use neutrophil destruction of microbes as an example.
- Neutrophil recognition of the microbe via sensors.
- The neutrophil engulfs the microbe and moves it into a phagosome.
- Lysosomes merge with the phagosome, which exposes the microbe to lysosomal degradative enzymes in a phagolysosome.
- Lysosomal enzymes, reactive oxygen species (ROS, aka, reactive oxygen intermediates), and inducible nitric oxide (iNO) destroy the microbe.
– Inflammatory cytokines, such as interferon gamma, trigger the production of ROS and iNO within the lysosomes and phagolysosomes.
Macrophages
Although neutrophils are the primary leukocytes active in acute inflammation, other cell types, particularly macrophages, have important roles.
Macrophages release both pro- and anti-inflammatory cytokines that mediate the inflammatory response; they also release growth factors and enzymes that promote tissue repair. We learn more about the complex actions of macrophages, elsewhere.
Control and Termination
Control and, ultimately, termination of the acute inflammatory response is necessary to avoid destruction of healthy host cells. Thus, it is not surprising that the mechanisms for control are built into the process:
Neutrophils have short half-lives outside of the blood stream, so their destructive capabilities in the tissues are limited.
Lipoxins, which are secreted by neutrophils and macrophages, prohibit continued recruitment of new neutrophils.
Also, as we mentioned earlier, macrophages release various anti-inflammatory molecules.
Possible outcomes of acute inflammation
Full resolution: return to normal tissue functioning is possible.
Scarring or fibrosis: the damaged tissues are replaced by connective tissues.
Chronic inflammation: inflammatory agents persist; we'll learn more about chronic inflammation, elsewhere.
Pharmacological correlation
NSAIDS – non-steroid anti-inflammatory drugs – inhibit cyclooxygenase (COX), which is the enzyme responsible for prostaglandin synthesis.
By inhibiting COX production, these medications, which include aspirin and ibuprofen, limit inflammation and pain. Elsewhere, we'll learn their affects on blood coagulation.
Signs of Acute Inflammation
Redness is caused by vasodilation and increased blood flow to the inflamed area.
Heat is also the result of vasodilation; pyrogens, including some bacterial products, are fever-inducing substances that act at the hypothalamus to re-set the body's basal temperature.
Swelling is the result of vessel leakage and edema during leukocyte and plasma protein recruitment.
Pain is caused by the release of prostaglandins and bradykinin.