Inflammatory Basis of Pulmonary Arterial Hypertension

Implications for Perioperative and Critical Care Medicine

Neil M. Goldenberg, M.D., Ph.D.; Marlene Rabinovitch, M.D.; Benjamin E. Steinberg, M.D., Ph.D.

Disclosures

Anesthesiology. 2019;131(4):898-907. 

In This Article

Future Immune Targets and Therapeutic Strategies in Pulmonary Arterial Hypertension

Although much debate continues on the topic of the primary insult that leads to pulmonary arterial hypertension, it is clear that the disease is characterized by smoldering inflammation.[69] This inflammation involves the totality of the immune system, affecting almost all known cell types and branches of immunity. It follows that therapeutic immune targeting necessitates restricted modulation of specific immunologic responses to mitigate off-target effects and global immunosuppression. For example, preclinical work is investigating the use of biased agonists and antagonists that preferentially propagate or inhibit signaling down one of several downstream pathways, respectively.[70]

Our better understanding of pulmonary arterial hypertension as an immunologic disease will certainly usher in a new era of targeted therapies for this fatal condition and shift management away from vasodilation toward immunomodulation. This would parallel the history of asthma, another inflammatory lung disease. Before the 1900s, the mainstays of therapy were bronchodilators, ironically in the form of "anticholinergic cigarettes."[71] These treatments were relatively effective for acute exacerbations, but failed to address the root cause in the way that modern controller inhalers do. With the advent of newer drugs, but more importantly, with an understanding of the inflammatory nature of the disease, asthma management shifted toward immunotherapy, with steroids coming to the fore in the 1950s.[71] We see pulmonary arterial hypertension following a similar trajectory, with vasodilators maintaining a role, but immunomodulators taking over as mainstay therapy. Like asthma, pulmonary arterial hypertension is a clinical syndrome, encompassing a host of causative factors. As such, it is likely that a variety of treatments will be required to address the various causes of pulmonary arterial hypertension. New clinical trials should shed light on the feasibility of such treatments in the coming years, and active translational research will continue to feed this pipeline. New targeted therapies will hopefully begin to have substantive impacts upon patients experiencing this terrible disease.

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