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Chapter 24: Lipids: Lipid Mediators of Inflammation

You are studying the effects of a previously uncharacterized drug upon oral administration to experimental animals. Your tests involve examination of the effects of this compound within the gut following inducement of colitis-like symptoms. You find that administration of the drug to these animals leads to a reduction in the severity of inflammation in the gut and enhances a return to normal GI activity. Your test compound is most likely inducing the synthesis of which of the following compound?

A. LTB₄

B. LXA₄

C. PCI₂

D. PGE₂

E. TXA₂

Answer B: The lipoxin, LXA₄, inhibits polymorphonuclear leukocyte (PMN) chemotaxis, PMN-mediated increases in vasopermeability, and PMN adhesion and migration through the endothelium resulting in an attenuation of pro-inflammatory responses in the gut. LXA₄ also stimulates phagocytosis of apoptotic PMN by monocyte-derived macrophages, which represents the resolution phase of inflammatory events.

A defect in which of the following enzyme activities would impair the production of the lipoxins by the classic pathway (ie, nonaspirin triggered) in neutrophils?

A. COX-1

B. COX-2

C. 5-LOX

D. 12-LOX

E. 15-LOX

Answer C: In one of the classical pathways of lipoxin synthesis, the interactions between epithelial cells and neutrophils require the activities of both 15-LOX and 5-LOX. Within the epithelial cells, the PLA₂-mediated release of arachidonic acid serves as a substrate for 15-LOX and generates 15S-H(p)ETE. This latter compound will then diffuse out of the epithelial cells and be taken up by neutrophils where the activity of 5-LOX will then convert it into 15S-epoxytetraene, which is the precursor for LXA₄ synthesis.

The lipoxins are characterized as pro-resolving compounds because they promote the resolution of an inflammatory response. Which of the following activities is associated with this pro-resolution function?

A. activation of TNF-α secretion

B. inhibition of polymorphonuclear (PMN) cell apoptosis

C. inhibition of the action of TGF-β

D. reduction in neutrophil infiltration at the site of inflammation

E. stimulation of IL-8 release

Answer D: Lipoxins and epi-lipoxins inhibit neutrophils (PMN) chemotaxis, PMN-mediated increases in vasopermeability, and PMN adhesion and migration ...

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