Patrick Y. Lee

Maldaptation of the link between inflammation and bone turnover may be a key determinant of osteoporosis

Currently the etiology of osteoporosis is attributed to various endocrine, metabolic, and mechanical factors. We hypothesize that many cases of osteoporosis are also partially attributable to a maladaptation of the link between inflammation and bone turnover. We explore the spatial and temporal link between inflammation and osteoporosis in conditions such as aging, menopause, reflex sympathetic dystrophy, HIV, pregnancy, transplantation, and steroid administration. While nutritional and mechanical factors clearly play a role in many of these situations, the spatial and temporal concordance of osteoporosis and inflammation is buttressed by emerging molecular evidence. Modern bone biology of humans may reflect dual functional legacies of mineral storage and structural support. Osteoporosis may result from disequilibrium between structural demand for key minerals and their biologic demand during maladaptive states of inflammation.

Autonomic dysregulation as a basis of cardiovascular, endocrine, and inflammatory disturbances associated with obstructive sleep apnea and other conditions of chronic hypoxia, hypercapnia, and acidosis

Obstructive sleep apnea has traditionally been viewed as a structural disease. A multitude of systemic endocrine and cardiovascular abnormalities have been previously attributed to the prevalence of obesity in these patients. A growing body of clinical evidence, however, points to a relationship between sleep apnea and its systemic abnormalities independent of obesity. We hypothesize that this association is based on a maladaptive autonomic response of chemoreceptors, reacting to the hypoxia, hypercapnia, and acidosis of sleep apnea. The elevated sympathetic response triggers an inflammatory cascade that results in a myriad of downstream consequences including insulin resistance, hypertension, diabetes, atherosclerosis and metabolic syndrome. The sympathetic bias and endocrine disturbances may further exacerbate sleep disturbance in a potentially pernicious cycle. Our proposal may extend to any chronic respiratory or metabolic conditions that manifest hypoxia, hypercapnia, and acidosis and elicit a maladaptive autonomic and inflammatory response.

Integrating Systems Biology and Medical Imaging: Understanding Disease Distribution in the Lung Model

OBJECTIVE Many chronic diseases exhibit characteristic pulmonary distribution patterns, but the underlying biologic explanations remain elusive. On the basis of emerging evidence from systems biology, we propose that gradients of T helper immune function exist as an epiphenomenon of the hypoxic pulmonary vasoconstriction response. Regional variation of immune function may contribute to preferential distribution patterning of lung diseases. CONCLUSION The lungs represent but one example in which the distribution of immune function throughout the body may explain disease location. This hypothetic framework can apply to diseases outside the realm of pulmonary biology and illustrates the potential benefit of integrating advances in systems biology and medical imaging.

Negative pressure ventilation via diaphragmatic pacing: a potential gateway for treating systemic dysfunctions

Programmed diaphragmatic pacing using implanted neuromodulators represents an emerging method for providing pulmonary support using negative pressure ventilation. The implantable, rechargeable, programmable and miniaturized nature of diaphragmatic pacers may obviate many of the management issues associated with noninvasive positive pressure ventilation devices. Closed loop systems may facilitate the implementation of diaphragmatic pacing for the treatment of many indications. They may allow for wider adoption of ventilatory support in central sleep apnea and improve quality of life in diseases of chronic hypoventilation, such as amyotrophic lateral sclerosis. In addition, it might alleviate subclinical hypoventilation – a condition that may affect a significant proportion of the aging population. Diaphragmatic pacing could also reduce sympathetic bias, which may contribute to a wide range of diseases associated with autonomic dysfunction.