© 2002 American Thoracic Society
Idiopathic Pneumonia after Marrow TransplantationWhen Are Antioxidants Effective?University of Minnesota Minneapolis, Minnesota Bone marrow transplantation is performed to salvage patients from imminent death following exposure to lethal doses of radiochemotherapy. Recipients may be infused with their own marrow cells (autologous) or related/unrelated marrow cells from the same species (allogeneic). Whenever feasible, autologous transplantation is preferred because genetically mismatched donor T cells may cause graft-versus-host disease. Nevertheless, recipients of autologous transplantation can develop drug-related, noninfectious diffuse lung dysfunction, termed "idiopathic pneumonia syndrome." In this issue of AJRCCM (pp. 1579–1589), Bhalla and Folz (1) introduce a novel animal model, simulating the human disease, to investigate mechanisms of idiopathic pneumonia syndrome after autologous marrow transplantation. The study of Bhalla and Folz (1) adds to the growing body of evidence that idiopathic pneumonia syndrome is the result of persistent proinflammatory events and oxidant responses (2–4). Results indicate that infusion of cytotoxic drugs activate pulmonary epithelial cells and macrophages to generate proinflammatory chemokines, including monocyte chemoattractant protein-1, which recruit and stimulate monocytes to generate a variety of inflammatory mediators and toxic reactive species. Similar events have been described after allogeneic marrow transplantation (5, 6). A major difference between the two types of transplantation, however, is the "second wave" of robust donor T cell-dependent inflammation that is only observed in recipients of allogeneic grafts. Data presented by Bhalla and Folz (1) show a gradual, time-dependent resolution of lung injury and cellular infiltration after transplantation, raising the possibility that a second event, such as exposure to irradiation or additional chemotherapy, may be necessary for the development of idiopathic pneumonia syndrome after autologous transplantation. The authors convincingly demonstrate that the main mechanism of chemotherapy-induced generation of oxidative stress is modifications of the glutathione system. This system includes the enzymes glutathione peroxidase and reductase, which maintain a high ratio of reduced to oxidized glutathione and a favorable redox state. Reduced glutathione is the major antioxidant in the lung and its concentration in the human epithelial lining fluid is 140-fold higher than in plasma (7). The authors show that one dose of cyclophosphamide/cisplatin is enough to acutely deplete total (reduced plus oxidized) glutathione, while bischloroethylnitrosourea inhibits glutathione reductase and increases the fraction of oxidized glutathione. The shift towards a more oxidizing state may trigger multiple inflammatory signal transduction pathways (8). Therefore, measurement of glutathione redox potential and oxidant/antioxidant balance in the lavage fluid may prove to be a clinically meaningful, simple, and accurate method to monitor pathophysiologic events in the respiratory system. In recipient mice given high-dose chemotherapy, treatment with n-acetylcysteine caused repletion of glutathione stores and partial attenuation of the increase in lavage fluid total protein and lactic dehydrogenase. As discussed by the authors, the most likely mechanism for the protective effects of n-acetylcysteine is indirect antioxidant activity by replenishment of glutathione redox potential, although direct scavenging of reactive species or antiinflammatory effects of n-acetylcysteine may have also contributed (9). A word of caution regarding the use of n-acetylcysteine during oxidant-mediated diseases is warranted, because the hydrogen atom of the free sulhydryl group of n-acetylcysteine may be extracted by radical intermediates to generate a thiyl radical that can further propagate free radical reactions (10). Despite the well documented damaging effects of oxidative stress, treatment of human oxidant-induced diseases with antioxidants including n-acetylcysteine has yielded disappointing results (11). Although suboptimal dosing, inappropriate timing of administration, and failure to reach the site of action are among cited reasons for lack of efficacy of antioxidants in clinical trials, emerging evidence indicates that oxidative stress also modulates immune responses. For example, patients with chronic granulomatous disease, an inherited disorder caused by defects in respiratory burst oxidase, develop severe noninfectious inflammatory granulomas in lung, skin, and gastrointestinal tract (12). In a model of allogeneic marrow transplantation, Yang and coworkers (13) observed exuberant pulmonary and systemic inflammation in irradiated mice lacking phagocytic nicotinamide adenine dinucleotide phosphate-oxidase, a major source of reactive oxygen species, compared with wild type mice. Importantly, exaggerated immune-responses in nicotinamide adenine dinucleotide phosphate-oxidase–deficient mice were associated with suppression of oxidative/nitrative stress, increased serum and lavage fluid levels of the proinflammatory chemokine, monocyte chemoattractant protein-1, and impaired clearance of exogenous recombinant macrophage inflammatory protein-1ß from the circulation. These results indicate that oxidative stress can function to suppress tissue-damaging inflammatory responses by inactivation of chemokines in vivo. How can we resolve the contradictory effects of oxidants in the study of Bhalla and Folz (1) and the study of Yang and coworkers (13)? During inflammatory lung diseases an optimal level of oxidative stress may exist where oxidant-induced damage is minimal and oxidant-mediated inactivation of proinflammatory chemokines is maximal. Inhibition of oxidative stress below this threshold level may impair the clearance of chemokines and exacerbate inflammation. Total inhibition of oxidant production may also be detrimental because of the important physiologic roles of reactive oxygen species in regulating the redox state, which is critical for cell growth/differentiation (14). The results of Bhalla and Folz show that attenuation of lung injury and cellular lung infiltration in chemotherapy recipient mice after n-acetylcysteine were associated with incomplete resolution of lipid peroxidation (evidence for persistence of low level oxidative stress). Taken together, these results are consistent with the notion that extreme inhibition of reactive oxygen species is best avoided. Maintaining a threshold level of oxidative stress can be beneficial, especially during chemokine-driven inflammatory diseases. The challenge remains to accurately estimate the extent of oxidative stress required to inactivate inflammatory mediators without causing significant effector oxidant-mediated injury. In summary, the animal model developed by Bhalla and Folz clearly implicates inflammatory and oxidant responses in the pathogenesis of idiopathic pneumonia syndrome after autologous marrow transplantation. This and similar animal models will enhance our knowledge of the multiple in vivo roles of oxidative stress. Understanding potential beneficial functions for reactive oxygen species during lung inflammation is arguably as important as determining mechanisms of injury by oxidative stress. The goal is to optimize our current strategies for using antioxidants for the prevention and treatment of idiopathic pneumonia syndrome and other inflammatory diseases affecting the respiratory system. REFERENCES
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