Pulmonary hypertension: Pathophysiology beyond the lung.

Pulmonary hypertension (PH) is classically considered a disease of pulmonary vasculature which has been the predominant target for drug development and PH therapy. Despite significant advancement in recent years in identification of new drug targets and innovative treatment strategies, the prognosis of PH remains poor, with median survival of 5 years. Recent studies have demonstrated involvement of neuroinflammation, altered autonomic and gastrointestinal functions and increased trafficking of bone marrow-derived cells in cardiopulmonary pathophysiology. This has led to the proposal that PH could be considered a systemic disease involving complex interactions among many organs. Our objectives in this review is to summarize evidence for the involvement of the brain, bone marrow and gut in PH pathophysiology. Then, to synthesize all evidence supporting a brain-gut-lung interaction hypothesis for consideration in PH pathophysiology and finally to summarize unanswered questions and future directions to move this novel concept forward. This forward-thinking view, if proven by further experiments, would provide new opportunities and novel targets for the control and treatment of PH.