Adverse Effects of Neutrophils on the Lung JAMES E. GADEK, M.D., Columbus,Ohio
Studies of both emphysema and adult respiratory distress syndrome (ARDS) support the premise that lung injury is due to unregulated host defense mechanisms. A major mediator of host defense and injury is the neutrophil, which is relatively incapable of regulating its own function. Accordingly, defects in regulatory mechanisms allow neutrophils to damage the lungs. Emphysema serves as a prime example of this link between host defense and injury. Hereditary emphysema is caused by a deficiency in al-antitrypsin (al-AT), a protease inhibitor. The decreased levels of this enzyme in affected individuals result in inadequate protection against neutrophil elastase and other proteolytic enzymes, leading to lung damage. Patients with acquired emphysema, associated with cigarette smoking, have normal levels of al-AT in their lungs. However, the al-AT in these patients has a reduced ability to associate with and inhibit the action of neutrophil elastase. Thus, both types of emphysema involve an alteration in the balance between proteases and antiproteases. The lung damage observed in patients with ARDS also appears to involve neutrophils, but in this case elastase may not be the culprit. In these patients, neutrophil elastase appears to be inactivated by high levels of al-AT, thus preventing excess protease action. It is hoped that a more complete understanding of the mechanisms involved in host defense and injury will enable the development of specific therapeutic interventions, such as the al-AT replacement therapy that is being used to treat patients with hereditary emphysema.
From the Department of Pulmonary and Critical Care Medicine, School of Medicine, The Ohio State University, Columbus, Ohio. Requests for reprints should be addressed to James E. Gadek,M.D.,The Ohio State University, N325 Means Hall, 1654 Upham Drive, Columbus, Ohio 43210.
host defense mechanisms can be as damaging to the human body as are the insults Ithatronically, these defense mechanisms have evolved to protect against. For example, the lungs, which act as a strategic "skirmish line" in host defense, are a primary site of damage caused by host defense mechanisms. At least some of this damage is expressed at the cellular level. Neutrophils are major mediators of both host defense and, when inappropriately regulated, host injury. In particular, neutrophils have been implicated in the lung damage found in patients with emphysema and adult respiratory distress syndrome (ARDS). The realization that a hereditary form of emphysema was associated with a deficiency in al-antitrypsin (al-AT), a protease inhibitor that regulates the activity of neutrophil elastase, resulted in the development of the protease-antiprotease theory of lung damage. In addition to al-AT deficiency, studies of acquired emphysema and ARDS have shown that the balance between proteases and antiproteases in the lungs can also be altered by other biologic mechanisms. A complete understanding of the pathogenesis of lung injury may allow therapies to be designed that prevent the destruction of tissue while retaining host defense capabilities.
NEUTROPHILS AND THE PATHOGENESISOF LUNG DISEASE Neutrophils play a vital role in protecting the lungs from microorganisms. However, these cells have very little capacity for controlling their own function; thus, regulatory cells and factors are required to keep them from harming the lung. When these protective mechanisms are deficient, lung damage can result. Neutrophils have two major means by which they can cause harm to their host (Figure 1). The first is by the release of proteases. Ordinarily, these enzymes enable the neutrophils to reach areas where microorganisms or other host defense stimuli exist. However, as will be shown, the release of these enzymes in an unregulated fashion results in the random destruction of host cells. The second way in which neutrophils can cause damage is by the production of reactive oxygen species, which can harm cells by both direct and indirect means.
June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A)
6A-27S
SYMPOSIUM ON ANTIMICROBIAL THERAPY / GADEK
Proteases The major protease that has been implicated in the pathogenesis of lung injury is neutrophil elastase, which is expressed when neutrophils are recruited to defend lung tissues from microorganisms or other irritants. Neutrophil elastase is an omnivorous enzyme that is capable of digesting virtually every connective tissue component of the lung. This enzyme can be thought of as a "drill" that allows the neutrophil to leave the vascular space and to gain access to microorganisms or other host defense stimuli that may be hidden deep within tissues. The ability of neutrophils to migrate to the areas where they are needed is essential to host defense; in the absence of elastase, chronic pulmonary and cutaneous infection may reflect loss of this proteolytic mechanism for extravascular access to pathogens. Collagenase is another enzyme in the neutrophil's host defense arsenal. Like elastase, this enzyme c a n cause extensive matrix damage if left unchecked. The major means by which unregulated release of collagenase damages organs is by interfering with tissue repair. Restoration of structure during the repair process depends on the maintenance of an intact and true template of the original structure. The presence of a neutrophil with collagenase activity in an area that is undergoing repair may not only interfere directly with the repair process by digesting collagen that is needed to seal the wound, but may interfere indirectly by disrupting repair and destroying the lung tissue needed to maintain the original structural picture [1]. It is essential that both elastase and collagenase, which are required for host defense, be carefully regulated to prevent them from damaging the tissues that they are trying to protect. One way that the body accomplishes this regulation is by means of antiproteases (protease inhibitors) that focus proteolytic activity on the area where their action serves host defense. An appropriate equilibrium between proteases and antiproteases is essential to maintaining the health and integrity of the lung;
~. Connective ~
Collagenase
tissue proteases ~
Elastase
_Oxidants 02
-,OH H202 Myeloperoxidase(MPO)
MPO+ H202+ X
oHXO
Figure 1. Oxidative and proteolytic mediators of lung damage that are released b
neutrophils. 6A-28S
factors that alter this balance can result in severe damage to the host.
Reactive OxygenSpecies Neutrophils produce a number of short-lived reactive oxygen species, including hydrogen peroxide, hydroxyl radicals, and superoxide anions. Additional species are produced in response to neutrophil myeloperoxidase, which combines with hydrogen peroxide and halides to generate chloramine, hypochlorous acid, and other reactive species. Reactive oxygen species contribute to the pathogenesis of lung damage in a number of different ways [1]. These species can mediate reactions that impair antiprotease action or that activate proteases, thus upsetting the protease-antiprotease balance. In addition, these compounds can attack the lung~s matrix proteins and cause direct damage to the lung.
EMPHYSEMA Emphysema serves as a prototype of lung damage caused by unregulated neutrophil action. This disease is marked by chronic, progressive, irreversible enlargement of the alveoli that lie distal to the terminal bronchioles. The destruction of the capillary network in the alveolar walls subverts the gas exchange process and causes physiologic impairment. There are two major forms of emphysema: hereditary emphysema, which is due to a deficiency in the amount or activity of arAT, a potent protease inhibitor; and acquired emphysema, normally associated with cigarette smoking.
Hereditary Emphysema Approximately 1-2% of cases of emphysema are due to al-AT deficiency [2]. This form of emphysema has an autosomal codominant pattern of expression and is marked by a]-AT serum levels that are
Studies of both emphysema and adult respiratory distress syndrome (ARDS) support the premise that lung injury is due to unregulated host defense mechanisms. A major mediator of host defense and injury is the neutrophil, which is relatively incapable of regulating its own function. Accordingly, defects in regulatory mechanisms allow neutrophils to damage the lungs. Emphysema serves as a prime example of this link between host defense and injury. Hereditary emphysema is caused by a deficiency in al-antitrypsin (al-AT), a protease inhibitor. The decreased levels of this enzyme in affected individuals result in inadequate protection against neutrophil elastase and other proteolytic enzymes, leading to lung damage. Patients with acquired emphysema, associated with cigarette smoking, have normal levels of al-AT in their lungs. However, the al-AT in these patients has a reduced ability to associate with and inhibit the action of neutrophil elastase. Thus, both types of emphysema involve an alteration in the balance between proteases and antiproteases. The lung damage observed in patients with ARDS also appears to involve neutrophils, but in this case elastase may not be the culprit. In these patients, neutrophil elastase appears to be inactivated by high levels of al-AT, thus preventing excess protease action. It is hoped that a more complete understanding of the mechanisms involved in host defense and injury will enable the development of specific therapeutic interventions, such as the al-AT replacement therapy that is being used to treat patients with hereditary emphysema.
From the Department of Pulmonary and Critical Care Medicine, School of Medicine, The Ohio State University, Columbus, Ohio. Requests for reprints should be addressed to James E. Gadek,M.D.,The Ohio State University, N325 Means Hall, 1654 Upham Drive, Columbus, Ohio 43210.
host defense mechanisms can be as damaging to the human body as are the insults Ithatronically, these defense mechanisms have evolved to protect against. For example, the lungs, which act as a strategic "skirmish line" in host defense, are a primary site of damage caused by host defense mechanisms. At least some of this damage is expressed at the cellular level. Neutrophils are major mediators of both host defense and, when inappropriately regulated, host injury. In particular, neutrophils have been implicated in the lung damage found in patients with emphysema and adult respiratory distress syndrome (ARDS). The realization that a hereditary form of emphysema was associated with a deficiency in al-antitrypsin (al-AT), a protease inhibitor that regulates the activity of neutrophil elastase, resulted in the development of the protease-antiprotease theory of lung damage. In addition to al-AT deficiency, studies of acquired emphysema and ARDS have shown that the balance between proteases and antiproteases in the lungs can also be altered by other biologic mechanisms. A complete understanding of the pathogenesis of lung injury may allow therapies to be designed that prevent the destruction of tissue while retaining host defense capabilities.
NEUTROPHILS AND THE PATHOGENESISOF LUNG DISEASE Neutrophils play a vital role in protecting the lungs from microorganisms. However, these cells have very little capacity for controlling their own function; thus, regulatory cells and factors are required to keep them from harming the lung. When these protective mechanisms are deficient, lung damage can result. Neutrophils have two major means by which they can cause harm to their host (Figure 1). The first is by the release of proteases. Ordinarily, these enzymes enable the neutrophils to reach areas where microorganisms or other host defense stimuli exist. However, as will be shown, the release of these enzymes in an unregulated fashion results in the random destruction of host cells. The second way in which neutrophils can cause damage is by the production of reactive oxygen species, which can harm cells by both direct and indirect means.
June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A)
6A-27S
SYMPOSIUM ON ANTIMICROBIAL THERAPY / GADEK
Proteases The major protease that has been implicated in the pathogenesis of lung injury is neutrophil elastase, which is expressed when neutrophils are recruited to defend lung tissues from microorganisms or other irritants. Neutrophil elastase is an omnivorous enzyme that is capable of digesting virtually every connective tissue component of the lung. This enzyme can be thought of as a "drill" that allows the neutrophil to leave the vascular space and to gain access to microorganisms or other host defense stimuli that may be hidden deep within tissues. The ability of neutrophils to migrate to the areas where they are needed is essential to host defense; in the absence of elastase, chronic pulmonary and cutaneous infection may reflect loss of this proteolytic mechanism for extravascular access to pathogens. Collagenase is another enzyme in the neutrophil's host defense arsenal. Like elastase, this enzyme c a n cause extensive matrix damage if left unchecked. The major means by which unregulated release of collagenase damages organs is by interfering with tissue repair. Restoration of structure during the repair process depends on the maintenance of an intact and true template of the original structure. The presence of a neutrophil with collagenase activity in an area that is undergoing repair may not only interfere directly with the repair process by digesting collagen that is needed to seal the wound, but may interfere indirectly by disrupting repair and destroying the lung tissue needed to maintain the original structural picture [1]. It is essential that both elastase and collagenase, which are required for host defense, be carefully regulated to prevent them from damaging the tissues that they are trying to protect. One way that the body accomplishes this regulation is by means of antiproteases (protease inhibitors) that focus proteolytic activity on the area where their action serves host defense. An appropriate equilibrium between proteases and antiproteases is essential to maintaining the health and integrity of the lung;
~. Connective ~
Collagenase
tissue proteases ~
Elastase
_Oxidants 02
-,OH H202 Myeloperoxidase(MPO)
MPO+ H202+ X
oHXO
Figure 1. Oxidative and proteolytic mediators of lung damage that are released b
neutrophils. 6A-28S
factors that alter this balance can result in severe damage to the host.
Reactive OxygenSpecies Neutrophils produce a number of short-lived reactive oxygen species, including hydrogen peroxide, hydroxyl radicals, and superoxide anions. Additional species are produced in response to neutrophil myeloperoxidase, which combines with hydrogen peroxide and halides to generate chloramine, hypochlorous acid, and other reactive species. Reactive oxygen species contribute to the pathogenesis of lung damage in a number of different ways [1]. These species can mediate reactions that impair antiprotease action or that activate proteases, thus upsetting the protease-antiprotease balance. In addition, these compounds can attack the lung~s matrix proteins and cause direct damage to the lung.
EMPHYSEMA Emphysema serves as a prototype of lung damage caused by unregulated neutrophil action. This disease is marked by chronic, progressive, irreversible enlargement of the alveoli that lie distal to the terminal bronchioles. The destruction of the capillary network in the alveolar walls subverts the gas exchange process and causes physiologic impairment. There are two major forms of emphysema: hereditary emphysema, which is due to a deficiency in the amount or activity of arAT, a potent protease inhibitor; and acquired emphysema, normally associated with cigarette smoking.
Hereditary Emphysema Approximately 1-2% of cases of emphysema are due to al-AT deficiency [2]. This form of emphysema has an autosomal codominant pattern of expression and is marked by a]-AT serum levels that are
