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.


Anesthesiology. 2019;131(4):898-907. 

In This Article

Immunologic Basis of Pulmonary Arterial Hypertension

A large body of evidence from both human trials and pre-clinical models currently supports the fundamental immunologic underpinnings of pulmonary arterial hypertension, implicating both soluble and cellular immune mediators across the innate and adaptive immune systems.[30]

Cytokines such as tumor necrosis factor and interleukins 1β and -6 are all found in increased concentrations in the blood of pulmonary arterial hypertension patients as compared to controls,[8,31,32] and in some cases, these levels correlate with disease severity. For instance, circulating interleukin-6 serves as a high-fidelity marker of right ventricular dysfunction in pulmonary arterial hypertension[33] and is elevated in almost all human and animal studies of the disease. Other noncanonical immune mediators have similarly been implicated. In particular, the proinflammatory protein high mobility group box-1 is elevated in the lungs and plasma of patients with idiopathic and congenital heart disease–related pulmonary arterial hypertension.[34,35] High mobility group box-1 is notable in that it is able to activate both innate and adaptive immunity pathways.[36] As such, it represents an active area of research in pulmonary arterial hypertension pathogenesis, and its modulation may form the basis for novel therapeutics. To that end, encouraging preclinical work in rodent models of PH has demonstrated that high mobility group box-1 neutralization protects against disease development.[37]

Immune cells are also important drivers of pulmonary arterial hypertension. A broad histopathologic survey of lungs from patients with pulmonary arterial hypertension demonstrated significant perivascular and interstitial inflammation with immune cell infiltration, regardless of the cause of pulmonary arterial hypertension.[38] The immune cell types that circulate and infiltrate the lungs of patients with pulmonary arterial hypertension include B and T lymphocytes,[39–43] macrophages,[43] neutrophils,[44–46] dendritic cells,[7,43] and mast cells.[7,43] Interestingly, patients with pulmonary arterial hypertension have a different immune cellular landscape in their lungs as compared with those of control patients, which suggests a shift toward the adaptive immune system. Recruited immune cells not only represent a potential source of local and circulating cytokines, but also directly contribute to pulmonary vascular remodeling. The abnormal pulmonary adventitia and vessels can also secrete proinflammatory molecules that activate immune cells,[47] further amplifying this process. Taken together, positive feedback loops propagate inflammation within the vessel wall and perpetuate the vasculopathy of pulmonary arterial hypertension.

The immunologic basis of pulmonary arterial hypertension development continues to evolve as the disease itself progresses. Later in the course of the disease, the adaptive immune system grows in influence and a more complex network of immune reactions develops within the vessel wall. The importance of adaptive immunity in pulmonary arterial hypertension has been further highlighted in several recent preclinical studies.[48,49] Yet, the importance of adaptive immunity in clinical disease is not a new concept. More than two decades ago, idiopathic pulmonary arterial hypertension was speculated to represent an autoimmune disease.[50] This notion has since gained increasing traction. The lungs of patients with pulmonary arterial hypertension contain bronchus-associated lymphoid tissue[51] and tertiary lymphoid tissue[52] capable of producing autoantibodies in a self-sustained fashion. Although the importance of autoimmunity in pulmonary arterial hypertension may have been anticipated in connective tissue disease and other rheumatologic illnesses, it is unexpected to find self-reactive antibodies in patients with pulmonary arterial hypertension resulting from nonimmunologic disease states. Yet, as many as 60% of patients with idiopathic pulmonary arterial hypertension had circulating autoantibodies,[50] as do even a proportion of patients with congenital heart disease–related pulmonary arterial hypertension.[53] The antivascular autoantibodies that are produced in this tissue will be made in a self-sustained fashion in a germinal center.[52] Therefore, tissue destruction and inflammation can continue in the absence of the initial immune stimulus. This, along with epigenetic changes in parenchymal cells,[54] may well form the basis for the chronic, progressive nature of pulmonary arterial hypertension.