© 2004 American Thoracic Society
Lung Infection and the DiaphragmPlacing Basic Research in Clinical PerspectiveINSERM U408, Faculté Xavier Bichat Paris, France Our understanding of respiratory muscle dysfunction induced by sepsis has advanced markedly in the last 20 years: different mechanisms have been proposed (alterations in calcium homeostasis, mitochondrial dysfunction, and sarcolemal injury) and the role of several mediators (proinflammatory cytokines, reactive oxygen species, and nitric oxide) has been characterized (1). Despite these advances, however, several unresolved questions remain. In this issue of the Journal (pp. 679–686), Divangahi and coworkers show, for the first time, that Pseudomonas aeruginosa lung infection lasting for 7 days induces significant diaphragmatic weakness without change in the strength of hindlimb muscles (2). Because respiratory mechanics were unchanged during the entire experimental period, diaphragmatic fatigue seems an unlikely cause of the muscle weakness. This study sets the stage to discuss two clinically relevant features of respiratory muscle pathophysiology that are still relatively underinvestigated: the effects of infections arising in thoracic or abdominal organs; and the effects of chronic infections. Respiratory failure is a common complication of severe infectious or inflammatory processes originating in organs or tissues of the abdominal and thoracic cavities, such as peritonitis, pancreatitis, or pneumonia. These pathological conditions can theoretically affect the diaphragm directly by contiguity. Relatively few investigators have examined the effects of acute peritonitis and pancreatitis on the diaphragm in animals (3–6); they showed a significant reduction in diaphragmatic strength, as observed by Divangahi and coworkers (2) with lung infection. Preferential weakness of the respiratory muscle was also observed with necrotizing pancreatitis in rats (5), the only study investigating the effects of abdominal processes that compared the diaphragm and hindlimb muscles. In contrast with these data, systemic inoculation of two boluses of Escherichia coli endotoxin in hamsters produced equivalent decreases in the strength of the diaphragm and a fast-twitch peripheral muscle (7). Divangahi and coworkers (2) hypothesize that both muscle activity (sustained in the case of the diaphragm) and topographic proximity between the respiratory muscle and the inflamed lung could be responsible for its selective weakness. This is also probably true in the case of abdominal disorders. Diaphragmatic histology was normal and muscular levels of myeloperoxidase, a marker of neutrophil infiltration, did not increase in either the muscle of the Pseudomonas-infected animals (2) or in animals with pancreatitis and peritonitis (3, 5), thus excluding direct extension of the infectious/inflammatory process to the muscle. Anatomical proximity to the infectious site could, however, be responsible for direct exposure of the diaphragm to bacteria and/or inflammatory mediators synthesized in the infected organ via direct lymphatic spread (8). Another pathway might involve mediators synthesized by activated macrophages and/or mesothelial cells of the pleural or peritoneal surfaces of the muscle. These mediators could, in turn, act on the underlying diaphragm, as seen in the heart, where mediators released by the cardiac endothelium act on the underlying myocardium (9).
The results of Divangahi and coworkers (2), showing diaphragmatic impairment 7 days after the bacterial inoculum, are of clinical importance because long-lasting infections are common. Few investigators have examined the effects of chronic or semichronic infections on the respiratory muscles. Drew and associates (10) studied the effects of chronic visceral leishmaniasis on the diaphragm and hindlimb muscles of hamsters. They noted atrophy of all muscles and a selective loss in force of a hindlimb fast-twitch muscle, even after correction for the loss of muscle mass. The effects of long lasting infections are probably close to these of semistarvation, with progressive catabolism and degradation of contractile proteins possibly playing a greater role than in acute sepsis (1). Data from the study of Divangahi and coworkers (2) support the progressive nature of muscle impairment in that the Pseudomonas inoculum, which induced diaphragmatic weakness at 7 days, did not impair strength generation at 2 days. What is the role of known mediators of acute diaphragmatic dysfunction in chronic infectious impairment? Both tumor necrosis factor- The role of diaphragmatic weakness as a predisposing factor for ventilatory failure and/or to difficulties in weaning from mechanical ventilation raises important questions in the context of altered lung function secondary to chronic lung infection. Placing the muscle at rest protects the rat diaphragm against contractile failure induced by acute sepsis (13), although the effects of prolonged mechanical ventilation on a muscle with an already curtailed function because of prolonged infection are unknown. Controlled mechanical ventilation in rabbits decreases the generation of diaphragmatic strength per se at 24 hours, and this phenomenon is accentuated at 3 days in conjunction with apparent myofibril damage (14). An increased protease activity and augmented oxidative stress is observed in the rat diaphragm as early as 18 hours after controlled mechanical ventilation (15). If these biochemical alterations are prolonged or accentuated with time, as suggested by sequential analysis of gene expression patterns in immobilized soleus muscle in rats (16), they could mimic those induced by chronic infection. Therefore a deleterious additive and/or synergistic effect on the diaphragm between long-lasting infections and mechanical ventilation cannot be excluded. A time-dependent evaluation of diaphragmatic strength, mass, fiber-type composition, protein metabolism, and gene expression profile could help us to understand the molecular basis of the effects of chronic infections on the muscle and their interactions with mechanical ventilation. The experimental model of lung infection utilized by Divangahi and coworkers (2) could be a useful and interesting experimental tool in this setting. This model may help us find strategies to prevent or minimize the effects of chronic infections on the respiratory muscles. FOOTNOTES Conflict of Interest Statement: J.B. has no declared conflict of interest. REFERENCES
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and reactive oxygen species induce acute contractile dysfunction and stimulate muscle catabolism by increasing ubiquitin conjugation to muscle proteins (
B activation (