Chest
Volume 128, Issue 5, November 2005, Pages 3618-3624
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Opinions and Hypotheses
Neurohumoral Activation as a Link to Systemic Manifestations of Chronic Lung Disease

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COPD is a major cause of death and disability worldwide. Treatment of COPD improves lung function but is unlikely to slow the steady downhill course of the disease or reduce mortality. In COPD, numerous abnormalities can be found outside the lung. These include systemic inflammation, cachexia, and skeletal muscle dysfunction. Thus, COPD has been called a systemic disease. Convincing data demonstrate that COPD causes neurohumoral activation. By precedents derived from chronic heart failure and other diseases characterized by neurohumoral activation, we propose that the negative consequences of neurohumoral activation, namely inflammation, cachexia, effects on ventilation, and skeletal muscle dysfunction, give rise to a self-perpetuating cycle that contributes to the pathogenesis of COPD, and which may involve respiratory muscle dysfunction as well as systemic inflammation. This concept may further help explain the increased cardiovascular morbidity and mortality in COPD patients. Currently, little is known about the effect of treatments directed at neurohumoral activation and COPD. As this aspect of COPD becomes better understood, new insights may direct novel therapeutic approaches.

Section snippets

Peripheral Sympathetic Activation

Using microneurography of the peroneal nerve, direct evidence of marked peripheral sympathetic activation in patients with COPD and hypoxemia has recently been obtained.6 As compared with age- and sex-matched healthy control subjects, muscle sympathetic nerve activity was twice as high in the patients as compared to the control subjects. These results could not be explained by concomitant medication.6

Cardiac Sympathetic Activation

Volterrani and colleagues7 were the first to study heart rate variability in the time domain

METHODOLOGIC AND HISTORICAL NOTES

The importance of neurohumoral activation in COPD is not well recognized and is relatively neglected from an investigative perspective. Initially, the altered heart rate response in COPD patients to various maneuvers was explained by autonomic polyneuropathy.11 Stein et al10 were among the first to interpret altered heart rate variability in their patients with obstructive lung disease as evidence of sympathetic activation. That the concept of neurohumoral activation in COPD has not been

POSSIBLE MECHANISMS OF NEUROHUMORAL ACTIVATION IN COPD

Dyspnea, respiratory motor drive, and autonomic control are anatomically and functionally tightly coupled in the brainstem. Specifically the perception of respiratory discomfort is represented in the sensorimotor integration area of the limbic system that governs autonomic control,28 and central respiratory motor drive is linked with central sympathetic outflow in the brainstem.29 These central interactions speak to the construct that dyspnea and increased respiratory drive in COPD may be

CONSEQUENCES OF NEUROHUMORAL ACTIVATION: PRECEDENTS FROM CHRONIC HEART FAILURE AND OTHER DISEASES CHARACTERIZED BY NEUROHUMORAL ACTIVATION

In patients with chronic heart failure, sympathetic overactivity plays a central role in disease progression and poor prognostic outcomes. Sympathetic activation is associated with increased breathing frequency, increased dead space ventilation and exertional dyspnea,46, 47 impaired endothelial function with decreased exercise-induced vasodilatation in skeletal muscle, a decrease in the number of type 1 (slow, endurance) muscle fibers, cardiomyocyte injury and apoptosis, and catabolic/anabolic

POTENTIAL IMPLICATIONS OF NEUROHUMORAL ACTIVATION IN COPD

Symptoms such as shortness of breath and fatigue are remarkably similar in chronic heart failure and COPD patients.52 The undesired accompaniments of neurohumoral activation described in heart failure may also be relevant to the shortness of breath, fatigue, cachexia, and other stigmata that characterize the pathophysiology of COPD.52

The proposed concept does not replace well-established concepts of disease progression in COPD, such as airway inflammation due to inhaled noxious agents, lung

CONCLUSION

We have presented evidence supporting neurohumoral activation in patients with COPD. By precedents derived from chronic heart failure and other diseases characterized by neurohumoral activation, we propose that the well-established negative consequences of neurohumoral activation, namely inflammation, cachexia, effects on ventilation, and skeletal muscle dysfunction, give rise to a self-perpetuating cycle that contributes to the pathogenesis of COPD, which involves respiratory muscle

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