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Pulmonary arterial hypertension (PAH) is a severe occlusive vascular disease of the lungs that eventually leads to right heart failure and death. In the clinical classification of pulmonary hypertension (PH), PAH is defined as a primary disease of the pulmonary vasculature that is not secondary to left heart disease, thromboembolism, or other pulmonary diseases affecting the airways and/or the parenchyma (1). The underlying basis of PAH is intrinsic abnormalities of the pulmonary vascular cells including endothelial dysfunction favoring vasoconstriction; and remodeling, in part through endothelial-to-mesenchymal transition (2). Medications for systemic hypertension are considered to be useless for the treatment of PAH, which further highlights the specificity of PAH pathomechanisms and the need for innovative therapy for this disease. In 2000, loss-of-function mutations were discovered in the BMPR2 gene, which encodes bone morphogenetic protein receptor type II (BMPR-II). However, the penetrance of the mutations is low (20%) and 80% of sporadic PAH cases develop in the absence of the BMPR2 mutation (3); 15 years later, this discovery has not translated to treatment. However, clinical trials that aim to increase BMP signaling are ongoing (NCT01647945).
To explain the low penetrance of the mutation, a concept referred to as the "multiple-hit hypothesis" became popular in the PAH community. It was supposed that the evolution of pulmonary vascular disease originates with the interaction of BMPR2 mutations and one or more inciting stimuli. Because inflammation is described as a key player in PAH pathogenesis (4), it was assumed by some groups that BMPR2 mutations and inflammation interact to precipitate the clinical expression of the disease. Both in vitro and in vivo a complete negative feedback loop between IL-6 (a potent proinflammatory cytokine) and BMPR-II signaling was demonstrated, suggesting that an important consequence of BMPR2 mutations may be poor regulation of cytokines, and thus vulnerability to an inflammatory second hit (5). In this issue of the Journal (pp. 859-872), Soon and coworkers report that acute exposure to LPS, a bacterial compound that elicits strong inflammatory response through Toll-like receptor-4 (TLR4) signaling, increased lung and circulating IL-6 and KC (IL-8 analog) in Bmpr21/2 mice to a greater extent than in wild-type controls (6). Similarly, pulmonary artery smooth muscle cells (PASMCs) from Bmpr21/2 mice and patients with BMPR2 mutations produced higher levels of...