• 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.

DETAILS

Recognition of offending agents

• 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.

Other sensors are specialized to recognize signs of 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.

• Circulating proteins act as pattern recognition molecules that recognize invaders by their display of abnormal, non-self patterns.
  – For example: mannose-binding lectin protein binds to mannose, which is a characteristic microbial sugar; after binding, MBL facilitates microbe ingestion and activates the immune system.

Recruitment of plasma proteins and leukocytes from the blood

1. Vasodilation and increased permeability of the vessel wall:

• Occur in response to inflammatory mediators, importantly: histamine, prostaglandins, platelet activating factor (PAF), thromboxane A2 (generated from prostaglandins), bradykinin, and leukotrienes.

2. Plasma proteins and fluid exit the vessel (aka, exudation); this process can lead to excess fluids in the interstitial tissues, a condition called “edema.”
   – Clinical correlation: fibrinous pericarditis is a form of acute inflammation; as a result of the inflammatory response, fibrin and leukocytes infiltrate the pericardium (specifically the visceral pericardium, aka, the epicardium) and can cause “friction rub.”
3. Neutrophil recruitment from the blood involves: Capture, Rolling, Adhesion, Diapedesis, and Chemotaxic Migration.

• Capture:
  – Capture occurs via E-selectins, which are a type of cell adhesion molecule.
  – Cytokines, specifically Tumor Necrosis Factor (TNF) and Interleukin-1, upregulate the expression of E-selectins on the endothelial lining of the vessel.
  – Correspondingly, neutrophils express PSGL-1 (P-selectin glycoprotein ligand -1), which binds with selectins.
• Rolling:
  – Achieved via binding with P-selectins; their expression is upregulated by cytokines, thrombin, and histamine.
• Adhesion:
  – Firmer adhesion occurs when endothelial ICAM-1 (Intracellular Adhesion Molecule) binds with neutrophil LFA-1 ligands (Lymphocyte Function-Associated).
• Diapedesis:
  – The process of movement across the vessel wall typically occurs via the paracellular route, and is assisted by PECAM-1 (Platelet Endothelial Cell Adhesion Molecule).
  – Once outside of the vessel, neutrophils generate more cytokines, which further promotes the inflammatory response.
• Chemotaxic Migration:
  – Chemokines guide neutrophils to the site of inflammation along chemotactic gradients.

Phagocytosis and destruction of inflammatory agents

We’ll use neutrophil destruction of microbes as an example.

1. Neutrophil recognition of the microbe via sensors.
2. The neutrophil engulfs the microbe and moves it into a phagosome.
3. Lysosomes merge with the phagosome, which exposes the microbe to lysosomal degradative enzymes in a phagolysosome.
4. 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.

• NETs
  In addition to phagocytosis, neutrophils can produce extracellular traps (aka, NETs) to destroy infective pathogens.
  – In this process, the neutrophil exudes its nuclear materials to envelop the microbes in chromatin and concentrated antimicrobial peptides and enzymes.

• 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:

• In many cases, full resolution occurs, in which return to normal tissue functioning is possible.
• In others, scarring or fibrosis occurs, in which the damaged tissues are replaced by connective tissues.
• Chronic inflammation results when 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.