Figure 2.

Conceptual Framework for Therapeutic Targeting of Biomass for PAH

The ultimate goal of pulmonary arterial hypertension (PAH) therapeutics is restoration of normal blood flow and durable disease modification, which will require reducing the pathological biomass that obliterates the lumen of pulmonary arteries in PAH patients. This figure demonstrates 2 theoretic paths to reducing pathological biomass contextualized by examples of potential targets: (left) the inhibition of biomass expansion or (right) the augmentation of biomass dissolution (right). Once a lesion is established (middle vessel), disease modification will require shifting the biomass turnover equation such that dissolution exceeds formation. The dynamics of biomass turnover under pathological conditions are not fully elucidated, and, therefore, an unanswered question is whether the background rate of biomass dissolution is sufficiently high such that lesion regression would be feasible in a practical time frame if new biomass deposition was effectively neutralized. Current therapeutic development is largely focused on developing strategies that target fibroproliferative growth (ie, biomass expansion). An alternative and largely untapped approach could be activation of the intracellular and/or extracellular mechanisms involved in the disposal of biomass. For the extracellular matrix (ECM), this would involve secreted proteases (eg, matrix metalloproteinase [MMP]). For intracellular biomass, this would involve canonical systems such as proteosomal degradation and/or lysosomal digestion of macromolecules. This could also involve reprogramming of immune cells to remove cells and extracellular material. TGFB = transforming growth factor beta; TK = tyrosine kinase.