Nitric Oxide. NO, a soluble gas produced from arginine by the action of nitric oxide synthase (NOS), also participates in microbial killing. There are three different types of NOS: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). eNOS and nNOS are constitutively expressed at low levels, and the NO they generate acts to maintain vascular tone and as a neurotransmitter, respectively. iNOS, the type that is involved in microbial killing, is expressed when macrophages are activated by cytokines (e.g., IFN-γ) or microbial products, and induces the production of NO. In macrophages, NO reacts with superoxide (O2 • ) to generate the highly reactive free radical peroxynitrite (ONOO•) (
Fig. 3.7C ). These nitrogen-derived free radicals, similar to ROS, attack and damage the lipids, proteins, and nucleic acids of microbes and host cells.
In addition to its role as a microbicidal substance, NO produced by endothelial cells relaxes vascular smooth muscle and promotes vasodilation. It is not clear if this action of NO plays an important role in the vascular reactions of acute inflammation.
Granule Enzymes and Other Proteins. Neutrophils and monocytes contain granules packed with enzymes and anti-microbial proteins that degrade microbes and dead tissues and may contribute to tissue damage. These granules are actively secretory and thus distinct from classical lysosomes. Neutrophils have two main types of granules. The smaller specific (or secondary) granules contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase. The larger azurophil (or primary) granules contain MPO, bactericidal factors (such as defensins), acid hydrolases, and a variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases, proteinase 3). Phagocytic vesicles containing engulfed material may fuse with these granules (and with lysosomes, as described earlier), and the ingested materials are destroyed. In addition, both types of granules also undergo exocytosis (degranulation), leading to the extracellular release of granule contents.
Different granule enzymes serve different functions. Acid proteases degrade bacteria and debris within phagolysosomes, which are acidified by membrane-bound proton pumps. Neutral proteases are capable of degrading various extracellular components, such as collagen, basement membrane, fibrin, elastin, and cartilage, resulting in the tissue destruction that accompanies inflammatory processes. Neutrophil elastase combats infections by degrading virulence factors of bacteria. Macrophages also contain acid hydrolases, collagenase, elastase, phospholipase, and plasminogen activator.
Because of the destructive effects of granule enzymes, the initial leukocytic infiltration, if unchecked, can potentiate further inflammation by damaging tissues. These harmful proteases, however, are normally controlled by a system of anti-proteases in the serum and tissue fluids. Foremost among these is α1-anti-trypsin, which is the major inhibitor of neutrophil elastase. A deficiency of these inhibitors may lead to sustained action of leukocyte proteases, as is the case in patients with α1-anti-trypsin deficiency (Chapter 13).
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