Harpers

624 / CHAPTER 52Table 52–12. Proteinases of neutrophils andantiproteinases of plasma and tissues. 1ProteinasesElastaseCollagenaseGelatinaseCathepsin GPlasminogen activatorAntiproteinasesα 1 -Antiproteinase (α 1 -antitrypsin)α 2 -MacroglobulinSecretory leukoproteinase inhibitorα 1 -AntichymotrypsinPlasminogen activator inhibitor–1Tissue inhibitor of metalloproteinase1 The table lists some of the important proteinases of neutrophilsand some of the proteins that can inhibit their actions. Most ofthe proteinases listed exist inside neutrophils as precursors. Plasminogenactivator is not a proteinase, but it is included because itinfluences the activity of plasmin, which is a proteinase. The proteinaseslisted can digest many proteins of the extracellular matrix,causing tissue damage. The overall balance of proteinase:antiproteinaseaction can be altered by activating the precursors ofthe proteinases, or by inactivating the antiproteinases. The lattercan be caused by proteolytic degradation or chemical modification,eg, Met-358 of α 1 -antiproteinase inhibitor is oxidized by cigarettesmoke.the causation of emphysema. 2 -Macroglobulin is aplasma protein that plays an important role in thebody’s defense against excessive action of proteases; itcombines with and thus neutralizes the activities of anumber of important proteases (Chapter 50).When increased amounts of chlorinated oxidants areformed during inflammation, they affect the proteinase:antiproteinaseequilibrium, tilting it in favor ofthe former. For instance, certain of the proteinaseslisted in Table 52–12 are activated by HOCl, whereascertain of the antiproteinases are inactivated by thiscompound. In addition, the tissue inhibitor of metalloproteinasesand α 1 -antichymotrypsin can be hydrolyzedby activated elastase, and α 1 -antiproteinase inhibitorcan be hydrolyzed by activated collagenase and gelatinase.In most circumstances, an appropriate balanceof proteinases and antiproteinases is achieved. However,in certain instances, such as in the lung whenα 1 -antiproteinase inhibitor is deficient or when largeamounts of neutrophils accumulate in tissues because ofinadequate drainage, considerable tissue damage can resultfrom the unopposed action of proteinases.RECOMBINANT DNA TECHNOLOGYHAS HAD A PROFOUND IMPACTON HEMATOLOGYRecombinant DNA technology has had a major impacton many aspects of hematology. The bases of the thalassemiasand of many disorders of coagulation (Chapter51) have been greatly clarified by investigationsusing cloning and sequencing. The study of oncogenesand chromosomal translocations has advanced understandingof the leukemias. As discussed above, cloningtechniques have made available therapeutic amounts oferythropoietin and other growth factors. Deficiency ofadenosine deaminase, which affects lymphocytes particularly,is the first disease to be treated by gene therapy.Like many other areas of biology and medicine, hematologyhas been and will continue to be revolutionizedby this technology.SUMMARY• The red blood cell is simple in terms of its structureand function, consisting principally of a concentratedsolution of hemoglobin surrounded by a membrane.• The production of red cells is regulated by erythropoietin,whereas other growth factors (eg, granulocyte-and granulocyte-macrophage colony-stimulatingfactors) regulate the production of white bloodcells.• The red cell contains a battery of cytosolic enzymes,such as superoxide dismutase, catalase, and glutathioneperoxidase, to dispose of powerful oxidantsgenerated during its metabolism.• Genetically determined deficiency of the activity ofglucose-6-phosphate dehydrogenase, which producesNADPH, is an important cause of hemolytic anemia.• Methemoglobin is unable to transport oxygen; bothgenetic and acquired causes of methemoglobinemiaare recognized. Considerable information has accumulatedconcerning the proteins and lipids of the redcell membrane. A number of cytoskeletal proteins,such as spectrin, ankyrin, and actin, interact with specificintegral membrane proteins to help regulate theshape and flexibility of the membrane.• Deficiency of spectrin results in hereditary spherocytosis,another important cause of hemolytic anemia.• The ABO blood group substances in the red cellmembrane are complex glycosphingolipids; the immunodominantsugar of A substance is N-acetylgalactosamine,whereas that of the B substance isgalactose.• Neutrophils play a major role in the body’s defensemechanisms. Integrins on their surface membranesdetermine specific interactions with various cell andtissue components.• Leukocytes are activated on exposure to bacteria andother stimuli; NADPH oxidase plays a key role in theprocess of activation (the respiratory burst). Mutationsin this enzyme and associated proteins causechronic granulomatous disease.