5-lipoxygenase (5-LO) is the predominant enzyme in neutrophils. Themain product, 5-HETE, which is chemotactic for neutrophils, isconverted into a family of compounds collectively called leukotrienes.LTB4 is a potent chemotactic agent and activator of neutrophilfunctional responses, such as aggregation and adhesion of leukocytesto venular endothelium, generation of oxygen free radicals, andrelease of lysosomal enzymes.
The principal actions of lipoxins are to inhibit leukocyterecruitment and the cellular components of inflammation.Resolvins inhibit leukocyte recruitment and activation, in partby inhibiting the production of cytokines. Thus, the anti-inflammatory activity of aspirin is likely attributable to itsability to inhibit cyclooxygenases (see below) and, perhaps, tostimulate the production of resolvins.In addition to platelet stimulation, PAF causes vasoconstrictionand bronchoconstriction, and at extremely low concentrationsit induces vasodilation and increased venular permeability witha potency 100 to 10,000 times greater than that of histamine.TNF and IL-1 are two of the major cytokines that mediateinflammation; systemic responses include fever, loss of appetite, slow-wave sleep, the release of neutrophils into thecirculation, the release of corticotropin and corticosteroidsand, particularly with regard to TNF, the hemodynamic effectsof septic shock—hypotension, decreased vascular resistance,increased heart rate, and decreased blood pH
NO is synthesized from L-arginine by the enzyme nitric oxide synthase(NOS)- eNOS and nNOS are constitutively expressed at low levels andcan be activated rapidly by an increase in cytoplasmic calcium ions.Influx of calcium into cells leads to a rapid production of NO.
iNOS, incontrast, is induced when macrophages and other cells areactivated by cytokines (e.g., TNF, IFN-γ) or other agents.
Different granule enzymes serve different functions. Acid proteasesdegrade bacteria and debris within the phagolysosomes, in which anacid pH is readily reached. Neutral proteases are capable of degradingvarious extracellular components. These enzymes can attack collagen,basement membrane, fibrin, elastin, and cartilage, resulting in thetissue destruction that accompanies inflammatory processes. Neutralproteases can also cleave C3 and C5 directly, releasinganaphylatoxins, and release a kinin-like peptide from kininogen.Neutrophil elastase has been shown to degrade virulence factors of