Neutrophils and Adult Respiratory Distress Syndrome: Two Interlocking Perspectives in 1991
In 1983, a review article on neutrophils and adult respiratory distress syndrome (ARDS), which focused largely on the detrimental contributions of neutrophils in ARDS, was published in the AMERICAN REVIEW OF RESPIRAlORY DISEASE (1). In this issue of the REVIEW, Martin and colleagues (2) have published an important report that suggests the loss of potentially beneficial effects of neturophils may be a complicating factor in ARDS. Comparison of the two faces of the neutrophil, which appears to have both damaging (offensive) and protective (defensive) capabilities, yields considerable insight into the pathogenesis and/or potential treatment of ARDS. The case for neutrophil participation in the development of ARDS has substantially increased since 1983 (1). Numerous observations now collectively indicate a primary or contributing role for neutrophils in many cases of ARDS. The quantity of neutrophils is increased in the lungs of patients with ARDS (3). Neutrophils from the blood of patients with ARDS have been found to be activated (4), and a wide variety of neutrophil activators and primers are present in blood and lung lavages of patients with ARDS (5-8). Moreover, neutrophil reconstitution worsens ARDS, which develops in neutropenic patients (9). Furthermore, addition of stimulated neutrophils damages cultured lung endothelial cells and isolated perfused lungs by mechanisms that are blocked by addition of inhibitors of toxic products produced by neutrophils (i.e., oxygen radical scavengers and/or elastase inhibitors) (10-12). The interesting observation that patients with ARDS have increased levels of oxidized, and thereby inactivated, antiproteases (and the potent protease, elastase) in their lung lavages further heightens the potential damaging role of neutrophils, which are the only source of elastase and also notable generators of oxidants (13). Other factors from neutrophils appear to contribute to ARDS as well (14). Finally, neutrophil depletion prevents ARDS-like injury after injection of neutrophil activators in a variety of intact animal models (15). The report by Martin and coworkers AM REV RESPIR DIS 1991; 144:251-252
(2) reminds us that neutrophils also have helpful characteristics by specifically addressing the neutrophil's bactericidal capacity and ability to limit lung infections. They found that bactericidal activity, oxygen radical generation, and chemotaxis are deficient in "alveolar" neutrophils lavaged from lungs of patients with ARDS. They suggest that this alveolar neutrophil defect increases susceptibility to pulmonary infection. This is reasonable. It is well known that deficiencies in numbers of neutrophils are associated with an increased susceptibility to infection and that neutrophils that are deficient in their ability to make oxygen radicals do not kill bacteria effectively in vitro. The latter is best demonstrated in studies of children with chronic granulomatous disease (COD). Neutrophils from these individuals have abnormalities in their NADPH oxidase system and fail to generate O 2 radicals or kill bacteria normally in vitro (16, 17). These patients also have frequent and overwhelming infections without. other apparent deficits in immune function. The bactericidal deficiency found in alveolar neutrophils from patients with ARDS is less severe than the abnormality that occurs in neutrophils from patients with COD, and one can only speculate about the significance of this more modest impairment of neutrophil function in vivo. To wit, heterozygous carriers of COD have neutrophils with relatively severe defects in oxygen radical production and neutrophil killing ability in vitro but develop infections only infrequently (18). Despite this disparity, it is likely that the recognized perturbation in function of alveolar neutrophils is significant in patients with ARDS who may also be nutritionally and otherwise severely compromised. One must be intrigued about the cause of the decreased alveolar neutrophil function in ARDS patients. Clearly, neutrophil subpopulation issues are always problematic, and the authors have correctly noted this concern regarding possible selection biases (19,20). Timing of neutrophil studies may also be important because neutrophils that may have been active early in the onset of ARDS may
have lost their effectiveness by the time the syndrome is clinically manifest. The present approach of comparing blood, pulmonary artery, and alveolar neutrophils is a sound experimental design. The comparison indicates that systemic effects in ARDS cause some impairment of neutrophil function. Neutrophils collected from the pulmonary artery, despite having normal microbicidal activity, are already deficient in superoxide anion and hydrogen peroxide production. However, the trip out of the microcirculation into the alveoli takes an additional toll on the neutrophil that further reduces its functional activity and decreases bactericidal capacity. Obviously, the journey through the lung in ARDS may not be the same as in a simple infection such as a pneumonia (21). Ideally, when called to combat infection, neutrophils would not be activated until arrival at the site of infection. In ARDS, however, many neutrophil stimuli may be released into the circulation that activate and exhaust neutrophils before they have opportunity to focus their bactericidal weaponry on a specific target. As the authors also indicate, the possible effects of various therapeutic interventions (drugs and/or high concentrations of oxygen) on observed deficiencies in neutrophil function need further consideration. We found that bactericidal activity in blood neutrophils was actually increased in untreated, otherwise healthy patients with acute bacterial infections but then decreased following treatment (21). It is not clear whether this decrease is the result of treatment or, again, an issue of timing. By comparison, blood neutrophils from untreated patients with blood culture positive endocarditis had decreased bactericidal function that increased after antibiotic treatment (22). These and other observations suggest that mechanisms that normally augment neutrophil function during infection may be blunted by ARDS and/or treatment of patients with ARDS. We have considerable enthusiasm for identifying and eliminating various cellular and humoral mediators which purportedly cause acute lung injury, yet we 251
252
often neglectto consider the consequences of disturbing the protective functions of these same factors. Furthermore, the salubrious qualities of neutrophils may go well beyond their bactericidal qualities. For example, neutrophils may be instrumental in forming chemotaxins to recruit monocytes, initiating repair processes, altering inflammation, and/or stimulating antioxidant protection processes (23-27). Neutrophils also contain scavengers of oxidants and may have the ability, like erythrocytes (28), to inactivate and perhaps lessen injury from oxidants generated by themselves or other sources. This mechanism might be especially important in locations where antioxidants are usually not present in optimal concentrations (29). Indeed, with our present antibiotic arsenal, loss of these other advantageous functions may be more crucial than loss of the microbicidal activites of neutrophils. Interest in reducing the adverse effects of neutrophils has prompted investigation of a series of elegant pharmacologic approaches that have been carefully designed to limit neutrophil-mediated destruction. The approaches include strategies directed at reducing neutrophil adherence, inactivating neutrophil products, and even preventing generation of toxins by neutrophils (30-32). For example, specific ways of blocking neutrophil oxygen-radical generation that interfere with production at the NADPH oxidase level may be on the horizon. These agents should make it possible to render normal neutrophils in patients at risk for ARDS defective in ways which are similar to neutrophils from COD patients. As these new approaches are used, hope is raised that we will see the first decline in the persistent high rates of mortality in ARDS. However, we may then encounter a different set of problems that are less severe, but significant, and that are related to loss of key protective and/or reparative functions of neutrophils. The latter possibility mandates that every effort be made to develop highly reversible and selectively targeted drugs that decrease the harmful while retaining (or even enhancing) the beneficial effects of neutrophils. Achieving this delicate balance will be a challenge. However, if we are successful in treating ARDS, this new information will have a favorable impact on many other inflammatory disease processes,including ischemia-reperfusion disorders and arthritis. The present studies by Martin and associates (2) add meaningfully to this process. Nonetheless, we
EDITORIAL
recognize that our understanding of the role of neutrophils in ARDS is still incomplete from both offensive and defensive perspectives. JOHN E. REPINE, CONNIE J. BEEHLER,
M.D. M.D.
Webb-Waring Lung Institute University of Colorado Health Sciences Center Denver, Colorado References 1. Tate RM, Repine JE. Neutrophils and the adult respiratory distress syndrome. Am Rev Respir Dis 1983; 128:552-9. 2. Martin TR, Pistorese BP, Hudson LD, Maunder RJ. The function of lung and blood neutrophils in patients with the Adult Respiratory Distress Syndrome. Implications for the pathogenesis of lung infections. Am Rev Respir Dis 1991; 144:()()()-()()(). 3. Weiland JE, Davis WB, Holter JF, Mohammed JR, Dorinsky PM, Gadek JE. Lung neutrophils in the adult respiratory distress syndrome. Clinical and pathophysiologic significance. Am Rev Respir Dis 1986; 133:218-25. 4. Zimmerman BA, Renzetti AD, Hill HR. Functional and metabolic activity of granulocytes from patients with adult respiratory distress syndrome. Evidence for activated neutrophils in the pulmonary circulation. Am Rev Respir Dis 1983; 127:290- 300. 5. Hammerschmidt DE, WeaverLJ, Hudson LD, Craddock PR, Jacob HS. Association of complement activation and elevatedplasma-C5a with adult respiratory distress syndrome. Pathophysiological relevance and possible prognostic value. Lancet 1980; 1:947-9. 6. Rinaldo JE, Christman JW. Mechanisms and mediators of the adult respiratorydistresssyndrome. Clin Chest Med 1990; 11:621-32. 7. Tracey KJ, LowrySF,Cerami A. Cachetin/TNFalpha in septic shock and septic adult respiratory distress syndrome. Am Rev Respir Dis 1988; 138: 1377-9. 8. Parsons PE, Fowler AA, Hyers TM, Henson PM. Chemotactic activity in bronchoalveolar lavage fluid from patients with adult respiratory distress syndrome. Am RevRespirDis 1985; 132:490-3. 9. Rinaldo JE, Borovetz H. Deterioration of oxygenation and abnormal lung microvascular permeability during resolution of leukopenia in patients with diffuse lung injury. Am Rev Respir Dis 1985; 131:579-83. 10. Baird BR, Cheronis JC, Sandhaus RA, Berger EM, White CW, Repine JE. Oxygen metabolites and neutrophil elastase synergistically cause edematous injury in isolated rat lungs. J Appl Physiol 1986; 61:2224-9. 11. Sacks T, Moldow CF, Craddock PR, Bowers TK, Jacob HS. Oxygenradicals mediate endothelial cell damage by complement-stimulated granulocytes. An in vitro model of immune vascular damage. J Clin Invest 1978; 61:1161-7. 12. Shasby DM, VanBenthuysen KM, Thte RM, Shasby SS, McMurtry IF, Repine JE. Granulocytes mediate acute edematous lung injury in rabbits and isolated rabbit lungs perfused with phorbol myristate acetate: role of oxygenradicals. Am RevRespir Dis 1982; 125:443-7. 13. Cochrane CG, Spragg RG, Revak SD, Cohen AB, McGuire WW. The presence of neutrophil
elastase and evidence of oxidation activity in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome. Am Rev Respir Dis 1983; 127:S25-S27. 14. LonigroAJ, StephensonAH, SpragueRS. Role of arachidonic acid metabolites in the pathogenesis of acute lung injury. Adv Prostaglandin Thromboxane Leukotriene Res 1991; 21A:421-8. 15. Heflin AC Jr., Brigham KL. Prevention by granulocyte depletion of increased vascular permeability of sheep lung followingendotoxemia. J Clin Invest 1981; 68:1253-60. 16. Holmes B,Quie PG, Windhorst DB, Good RA. Fatal granulomatous disease of childhood. An inborn abnormality of phagocytic function. Lancet 1966; 1:1225-8. 17. Repine JE, White JG, Clawson CC, Holmes BM. Effects of phorbol myristate acetate on the metabolism and ultrastructure of neutrophils in chronic granulomatous disease. J Clin Invest 1974; 54:83-90. 18. Repine JE, Clawson CC, White JG, Holmes BM. Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease. J Pediatr 1975; 87:901-7. 19. Clement LT, Lehmeryer JE, Gartland GL. Identification of neutrophil subpopulations with monoclonal antibodies. Blood 1983; 61:326-32. 20. Gallin JL. Neutrophil heterogeneity exists, but is it meaningful? Blood 1984; 63:977-83. 21. Repine JE, Clawson CC, Goetz FC. Bactericidal function of neutrophils from patients with acute bacterial infections and from diabetics. J Infect Dis 1980; 142:869-75. 22. Repine JE, Clawson CC, Burchell HB, White JG. Reversible neutrophil defect in bacterial endocarditis. J Lab Clin Med 1976; 88:780-7. 23. Ward PA. Chemotaxis of mononuclear cells. J Exp Med 1968; 128:1201-21. 24. Weissmann G, Smolen JE, Korchak HM. Release of inflammatory mediators from stimulated neutrophils. N Engl J Med 1980; 303:27-34. 25. Wedmore CV, Williams TJ. Control of vascular permeability by polymorphonuclear leukocytes in inflammation. Nature 1981; 289:646-50. 26. Gallin JI, Fletcher MP, Seligmann BE, Hoffstein S, Lehrs K, Mounessa N. Human neutrophil specific granule deficiency: a model to assess the role of neutrophil specific granules in the evolution of the inflammatory response. Blood 1982; 59:1317-29. 27. Brown JM, White CW,TeradaLS,Grosso MA, Shanley PF, Mulvin DW, Banerjee A, Whitmann GJR, Harken AH, Repine JE. Interleukin-l pretreatment decreases ischemia-reperfusion injury. Proc Nat! Acad Sci USA 1990; 87:5026-30. 28. Toth KM, Clifford DP, White CW, Repine JE. Intact human erythrocytes prevent hydrogen peroxide mediated damage to isolated perfused rat lungs and cultured bovine pulmonary artery endothelial cells. J Clin Invest 1984; 74:292-5. 29. Berger EM, Beehler CJ, Harada RN, Repine JE. Human phagocytic cells as oxygen metabolite scavengers. Inflammation 1990; 14:613-9. 30. Riva CM, Morganroth ML, Ljungman AG, Schoeneich SO, Marks RM, Todd RF, Ward PA, BoxerLA. Iloprost inhibits neutrophil-induced lung injury and neutrophil adherence to endothelial monolayers. Am J Respir Cell Mol BioI 1990; 3:301-9. 31. Mandell GL. ARDS, neutrophils, and pentoxifylline. Am Rev Respir Dis 1988; 138:1103-5. 32. VolppBD, Nauseef WM, Clark RA. lWo cytosolie neutrophil oxidase components absent in autosomal chronic granulomatous disease. Science 1988; 242:1298-301.
In 1983, a review article on neutrophils and adult respiratory distress syndrome (ARDS), which focused largely on the detrimental contributions of neutrophils in ARDS, was published in the AMERICAN REVIEW OF RESPIRAlORY DISEASE (1). In this issue of the REVIEW, Martin and colleagues (2) have published an important report that suggests the loss of potentially beneficial effects of neturophils may be a complicating factor in ARDS. Comparison of the two faces of the neutrophil, which appears to have both damaging (offensive) and protective (defensive) capabilities, yields considerable insight into the pathogenesis and/or potential treatment of ARDS. The case for neutrophil participation in the development of ARDS has substantially increased since 1983 (1). Numerous observations now collectively indicate a primary or contributing role for neutrophils in many cases of ARDS. The quantity of neutrophils is increased in the lungs of patients with ARDS (3). Neutrophils from the blood of patients with ARDS have been found to be activated (4), and a wide variety of neutrophil activators and primers are present in blood and lung lavages of patients with ARDS (5-8). Moreover, neutrophil reconstitution worsens ARDS, which develops in neutropenic patients (9). Furthermore, addition of stimulated neutrophils damages cultured lung endothelial cells and isolated perfused lungs by mechanisms that are blocked by addition of inhibitors of toxic products produced by neutrophils (i.e., oxygen radical scavengers and/or elastase inhibitors) (10-12). The interesting observation that patients with ARDS have increased levels of oxidized, and thereby inactivated, antiproteases (and the potent protease, elastase) in their lung lavages further heightens the potential damaging role of neutrophils, which are the only source of elastase and also notable generators of oxidants (13). Other factors from neutrophils appear to contribute to ARDS as well (14). Finally, neutrophil depletion prevents ARDS-like injury after injection of neutrophil activators in a variety of intact animal models (15). The report by Martin and coworkers AM REV RESPIR DIS 1991; 144:251-252
(2) reminds us that neutrophils also have helpful characteristics by specifically addressing the neutrophil's bactericidal capacity and ability to limit lung infections. They found that bactericidal activity, oxygen radical generation, and chemotaxis are deficient in "alveolar" neutrophils lavaged from lungs of patients with ARDS. They suggest that this alveolar neutrophil defect increases susceptibility to pulmonary infection. This is reasonable. It is well known that deficiencies in numbers of neutrophils are associated with an increased susceptibility to infection and that neutrophils that are deficient in their ability to make oxygen radicals do not kill bacteria effectively in vitro. The latter is best demonstrated in studies of children with chronic granulomatous disease (COD). Neutrophils from these individuals have abnormalities in their NADPH oxidase system and fail to generate O 2 radicals or kill bacteria normally in vitro (16, 17). These patients also have frequent and overwhelming infections without. other apparent deficits in immune function. The bactericidal deficiency found in alveolar neutrophils from patients with ARDS is less severe than the abnormality that occurs in neutrophils from patients with COD, and one can only speculate about the significance of this more modest impairment of neutrophil function in vivo. To wit, heterozygous carriers of COD have neutrophils with relatively severe defects in oxygen radical production and neutrophil killing ability in vitro but develop infections only infrequently (18). Despite this disparity, it is likely that the recognized perturbation in function of alveolar neutrophils is significant in patients with ARDS who may also be nutritionally and otherwise severely compromised. One must be intrigued about the cause of the decreased alveolar neutrophil function in ARDS patients. Clearly, neutrophil subpopulation issues are always problematic, and the authors have correctly noted this concern regarding possible selection biases (19,20). Timing of neutrophil studies may also be important because neutrophils that may have been active early in the onset of ARDS may
have lost their effectiveness by the time the syndrome is clinically manifest. The present approach of comparing blood, pulmonary artery, and alveolar neutrophils is a sound experimental design. The comparison indicates that systemic effects in ARDS cause some impairment of neutrophil function. Neutrophils collected from the pulmonary artery, despite having normal microbicidal activity, are already deficient in superoxide anion and hydrogen peroxide production. However, the trip out of the microcirculation into the alveoli takes an additional toll on the neutrophil that further reduces its functional activity and decreases bactericidal capacity. Obviously, the journey through the lung in ARDS may not be the same as in a simple infection such as a pneumonia (21). Ideally, when called to combat infection, neutrophils would not be activated until arrival at the site of infection. In ARDS, however, many neutrophil stimuli may be released into the circulation that activate and exhaust neutrophils before they have opportunity to focus their bactericidal weaponry on a specific target. As the authors also indicate, the possible effects of various therapeutic interventions (drugs and/or high concentrations of oxygen) on observed deficiencies in neutrophil function need further consideration. We found that bactericidal activity in blood neutrophils was actually increased in untreated, otherwise healthy patients with acute bacterial infections but then decreased following treatment (21). It is not clear whether this decrease is the result of treatment or, again, an issue of timing. By comparison, blood neutrophils from untreated patients with blood culture positive endocarditis had decreased bactericidal function that increased after antibiotic treatment (22). These and other observations suggest that mechanisms that normally augment neutrophil function during infection may be blunted by ARDS and/or treatment of patients with ARDS. We have considerable enthusiasm for identifying and eliminating various cellular and humoral mediators which purportedly cause acute lung injury, yet we 251
252
often neglectto consider the consequences of disturbing the protective functions of these same factors. Furthermore, the salubrious qualities of neutrophils may go well beyond their bactericidal qualities. For example, neutrophils may be instrumental in forming chemotaxins to recruit monocytes, initiating repair processes, altering inflammation, and/or stimulating antioxidant protection processes (23-27). Neutrophils also contain scavengers of oxidants and may have the ability, like erythrocytes (28), to inactivate and perhaps lessen injury from oxidants generated by themselves or other sources. This mechanism might be especially important in locations where antioxidants are usually not present in optimal concentrations (29). Indeed, with our present antibiotic arsenal, loss of these other advantageous functions may be more crucial than loss of the microbicidal activites of neutrophils. Interest in reducing the adverse effects of neutrophils has prompted investigation of a series of elegant pharmacologic approaches that have been carefully designed to limit neutrophil-mediated destruction. The approaches include strategies directed at reducing neutrophil adherence, inactivating neutrophil products, and even preventing generation of toxins by neutrophils (30-32). For example, specific ways of blocking neutrophil oxygen-radical generation that interfere with production at the NADPH oxidase level may be on the horizon. These agents should make it possible to render normal neutrophils in patients at risk for ARDS defective in ways which are similar to neutrophils from COD patients. As these new approaches are used, hope is raised that we will see the first decline in the persistent high rates of mortality in ARDS. However, we may then encounter a different set of problems that are less severe, but significant, and that are related to loss of key protective and/or reparative functions of neutrophils. The latter possibility mandates that every effort be made to develop highly reversible and selectively targeted drugs that decrease the harmful while retaining (or even enhancing) the beneficial effects of neutrophils. Achieving this delicate balance will be a challenge. However, if we are successful in treating ARDS, this new information will have a favorable impact on many other inflammatory disease processes,including ischemia-reperfusion disorders and arthritis. The present studies by Martin and associates (2) add meaningfully to this process. Nonetheless, we
EDITORIAL
recognize that our understanding of the role of neutrophils in ARDS is still incomplete from both offensive and defensive perspectives. JOHN E. REPINE, CONNIE J. BEEHLER,
M.D. M.D.
Webb-Waring Lung Institute University of Colorado Health Sciences Center Denver, Colorado References 1. Tate RM, Repine JE. Neutrophils and the adult respiratory distress syndrome. Am Rev Respir Dis 1983; 128:552-9. 2. Martin TR, Pistorese BP, Hudson LD, Maunder RJ. The function of lung and blood neutrophils in patients with the Adult Respiratory Distress Syndrome. Implications for the pathogenesis of lung infections. Am Rev Respir Dis 1991; 144:()()()-()()(). 3. Weiland JE, Davis WB, Holter JF, Mohammed JR, Dorinsky PM, Gadek JE. Lung neutrophils in the adult respiratory distress syndrome. Clinical and pathophysiologic significance. Am Rev Respir Dis 1986; 133:218-25. 4. Zimmerman BA, Renzetti AD, Hill HR. Functional and metabolic activity of granulocytes from patients with adult respiratory distress syndrome. Evidence for activated neutrophils in the pulmonary circulation. Am Rev Respir Dis 1983; 127:290- 300. 5. Hammerschmidt DE, WeaverLJ, Hudson LD, Craddock PR, Jacob HS. Association of complement activation and elevatedplasma-C5a with adult respiratory distress syndrome. Pathophysiological relevance and possible prognostic value. Lancet 1980; 1:947-9. 6. Rinaldo JE, Christman JW. Mechanisms and mediators of the adult respiratorydistresssyndrome. Clin Chest Med 1990; 11:621-32. 7. Tracey KJ, LowrySF,Cerami A. Cachetin/TNFalpha in septic shock and septic adult respiratory distress syndrome. Am Rev Respir Dis 1988; 138: 1377-9. 8. Parsons PE, Fowler AA, Hyers TM, Henson PM. Chemotactic activity in bronchoalveolar lavage fluid from patients with adult respiratory distress syndrome. Am RevRespirDis 1985; 132:490-3. 9. Rinaldo JE, Borovetz H. Deterioration of oxygenation and abnormal lung microvascular permeability during resolution of leukopenia in patients with diffuse lung injury. Am Rev Respir Dis 1985; 131:579-83. 10. Baird BR, Cheronis JC, Sandhaus RA, Berger EM, White CW, Repine JE. Oxygen metabolites and neutrophil elastase synergistically cause edematous injury in isolated rat lungs. J Appl Physiol 1986; 61:2224-9. 11. Sacks T, Moldow CF, Craddock PR, Bowers TK, Jacob HS. Oxygenradicals mediate endothelial cell damage by complement-stimulated granulocytes. An in vitro model of immune vascular damage. J Clin Invest 1978; 61:1161-7. 12. Shasby DM, VanBenthuysen KM, Thte RM, Shasby SS, McMurtry IF, Repine JE. Granulocytes mediate acute edematous lung injury in rabbits and isolated rabbit lungs perfused with phorbol myristate acetate: role of oxygenradicals. Am RevRespir Dis 1982; 125:443-7. 13. Cochrane CG, Spragg RG, Revak SD, Cohen AB, McGuire WW. The presence of neutrophil
elastase and evidence of oxidation activity in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome. Am Rev Respir Dis 1983; 127:S25-S27. 14. LonigroAJ, StephensonAH, SpragueRS. Role of arachidonic acid metabolites in the pathogenesis of acute lung injury. Adv Prostaglandin Thromboxane Leukotriene Res 1991; 21A:421-8. 15. Heflin AC Jr., Brigham KL. Prevention by granulocyte depletion of increased vascular permeability of sheep lung followingendotoxemia. J Clin Invest 1981; 68:1253-60. 16. Holmes B,Quie PG, Windhorst DB, Good RA. Fatal granulomatous disease of childhood. An inborn abnormality of phagocytic function. Lancet 1966; 1:1225-8. 17. Repine JE, White JG, Clawson CC, Holmes BM. Effects of phorbol myristate acetate on the metabolism and ultrastructure of neutrophils in chronic granulomatous disease. J Clin Invest 1974; 54:83-90. 18. Repine JE, Clawson CC, White JG, Holmes BM. Spectrum of function of neutrophils from carriers of sex-linked chronic granulomatous disease. J Pediatr 1975; 87:901-7. 19. Clement LT, Lehmeryer JE, Gartland GL. Identification of neutrophil subpopulations with monoclonal antibodies. Blood 1983; 61:326-32. 20. Gallin JL. Neutrophil heterogeneity exists, but is it meaningful? Blood 1984; 63:977-83. 21. Repine JE, Clawson CC, Goetz FC. Bactericidal function of neutrophils from patients with acute bacterial infections and from diabetics. J Infect Dis 1980; 142:869-75. 22. Repine JE, Clawson CC, Burchell HB, White JG. Reversible neutrophil defect in bacterial endocarditis. J Lab Clin Med 1976; 88:780-7. 23. Ward PA. Chemotaxis of mononuclear cells. J Exp Med 1968; 128:1201-21. 24. Weissmann G, Smolen JE, Korchak HM. Release of inflammatory mediators from stimulated neutrophils. N Engl J Med 1980; 303:27-34. 25. Wedmore CV, Williams TJ. Control of vascular permeability by polymorphonuclear leukocytes in inflammation. Nature 1981; 289:646-50. 26. Gallin JI, Fletcher MP, Seligmann BE, Hoffstein S, Lehrs K, Mounessa N. Human neutrophil specific granule deficiency: a model to assess the role of neutrophil specific granules in the evolution of the inflammatory response. Blood 1982; 59:1317-29. 27. Brown JM, White CW,TeradaLS,Grosso MA, Shanley PF, Mulvin DW, Banerjee A, Whitmann GJR, Harken AH, Repine JE. Interleukin-l pretreatment decreases ischemia-reperfusion injury. Proc Nat! Acad Sci USA 1990; 87:5026-30. 28. Toth KM, Clifford DP, White CW, Repine JE. Intact human erythrocytes prevent hydrogen peroxide mediated damage to isolated perfused rat lungs and cultured bovine pulmonary artery endothelial cells. J Clin Invest 1984; 74:292-5. 29. Berger EM, Beehler CJ, Harada RN, Repine JE. Human phagocytic cells as oxygen metabolite scavengers. Inflammation 1990; 14:613-9. 30. Riva CM, Morganroth ML, Ljungman AG, Schoeneich SO, Marks RM, Todd RF, Ward PA, BoxerLA. Iloprost inhibits neutrophil-induced lung injury and neutrophil adherence to endothelial monolayers. Am J Respir Cell Mol BioI 1990; 3:301-9. 31. Mandell GL. ARDS, neutrophils, and pentoxifylline. Am Rev Respir Dis 1988; 138:1103-5. 32. VolppBD, Nauseef WM, Clark RA. lWo cytosolie neutrophil oxidase components absent in autosomal chronic granulomatous disease. Science 1988; 242:1298-301.
