Inhaled Treprostinil for Pulmonary Arterial Hypertension
Inhaled Treprostinil for Pulmonary Arterial Hypertension
The prostaglandin I2 receptor (IP), expressed on the surface of pulmonary artery smooth muscle cells (PASMCs), is the primary target of treprostinil and other prostacyclin analogs. In most circumstances, IP couples to a Gs protein; receptor stimulation activates adenylate cyclase to increase cyclic adenosine monophosphate (cAMP) levels. Opening of Ca-activated K channels, hyperpolarization, smooth muscle relaxation and vasodilation result.
In addition to IP, treprostinil activates the prostaglandin EP2 receptor, another Gs-coupled relaxant receptor. Unlike IP expression, which is notably downregulated in human and experimental PAH, EP2 expression appears to be preserved. Treprostinil is also capable of stimulating the EP3 receptor; by contrast, its downstream signaling leads to increased vascular tone. The importance of these alternative prostanoid receptors has not been fully defined.
Complex pulmonary vascular remodeling is a hallmark of PAH. Smooth muscle cell dysfunction and inappropriate growth and proliferation contribute to luminal narrowing and increased vascular resistance. In vitro, PASMCs isolated from patients with PAH demonstrate increased proliferation compared with cells from human controls. The mechanisms behind the disordered growth and remodeling are complex and incompletely understood. A significant reduction of IP on PASMCs from patients with PAH has been observed. Despite paucity of the IP receptor, treprostinil inhibits this aberrant growth in vitro; suppression was retained even with concurrent addition of a specific IP antagonist, indicating IP-independent pathways.
The work of Falcetti et al. also supports a role for peroxisome proliferator-activated receptor-γ (PPAR-γ) in smooth muscle hyperplasia in PAH. In vitro, treprostinil's antiproliferative effect on smooth muscle cells is significantly reduced with specific PPAR-γ blockade. Furthermore, growth suppression by treprostinil is potentiated by the PPAR-γ agonist rosiglitazone.
Prostacylin derivatives also participate in signaling pathways involving bone morphogenic proteins (BMPs), whose receptor BMPR-II is notably mutated in the majority of individuals with familial PAH. Stimulated BMPR-II on the surface of endothelial and smooth muscle cells affects transcription partly via inhibitors of DNA binding (Id) proteins. One antiproliferative subtype, Id1, is stimulated by prostanoids in both cell culture and the monocrotaline rat model. Thus, signaling pathways involving BMPs, BMPR-II and Ids also merit attention in discussion of the antiproliferative effects of the prostanoids.
Prostacyclin and its derivatives also inhibit platelet aggregation. This action is dependent on IP; IP-knockout mice demonstrate increased platelet activation in response to vascular damage.
VEGF, a major stimulator of angiogenesis, is elevated in patients with idiopathic and scleroderma-related PAH. It is not clear whether upregulation of pro-angiogenesis pathways is adaptive or part of the pathogenesis of the disease; however, the prostacyclin analogs do influence signaling. Beraprost and iloprost further upregulate VEGF in vitro and in mice. Similarly, initiation of intravenous treprostinil in 13 PAH patients was associated with an increase in VEGF.
Fontana et al. observed the effect of treprostinil on isolated rat ventricular myocytes in a single study. Treprostinil alone had a minimal effect on stimulated cell shortening; however, it potentiated the positive inotropy of the β-agonist isoprenaline. The mechanism of this effect, and its applicability to other prostanoids, has not been defined.
The role of inflammatory pathways in the pathogenesis of PAH is increasingly being investigated. Patients with PAH demonstrate elevated expression of several soluble mediators, including MCP-1, IL-1β, IL-6, fractalkine and RANTES.In vitro work focusing on PAH and other inflammatory diseases demonstrates decreased production of several proinflammatory cytokines and chemokines following exposure to treprostinil and other prostanoids. Treatment of PAH patients with intravenous epoprostenol is associated with significant decrease in serum MCP-1. Interestingly, interruption of MCP-1 signaling inhibits pulmonary hypertension progression in the monocrotaline rat model. Insight into how prostacyclin may mediate MCP-1 suppression has been recently described.
While targeted inhibition of inflammation could be beneficial in limiting pathologic progression, detrimental effects of prostanoid mediated immune suppression may also be clinically important. Treprostinil inhibits both phagocytosis and subsequent bacterial killing by macrophages in vitro; stimulation of the EP2 receptor appears to be particularly important in this process. Of interest, PAH patients treated with intravenous treprostinil infusions have higher rates of bacterial bloodstream infections, and Gram-negative bloodstream infections in particular, in comparison to those on intravenous epoprostenol. In theory, this may be due to more potent immunosuppression with treprostinil; an alternative explanation, emphasizing the effect of neutral versus alkaline pH of the diluents, also has supportive data.
Pharmacodynamics
Pulmonary Vasodilation
The prostaglandin I2 receptor (IP), expressed on the surface of pulmonary artery smooth muscle cells (PASMCs), is the primary target of treprostinil and other prostacyclin analogs. In most circumstances, IP couples to a Gs protein; receptor stimulation activates adenylate cyclase to increase cyclic adenosine monophosphate (cAMP) levels. Opening of Ca-activated K channels, hyperpolarization, smooth muscle relaxation and vasodilation result.
In addition to IP, treprostinil activates the prostaglandin EP2 receptor, another Gs-coupled relaxant receptor. Unlike IP expression, which is notably downregulated in human and experimental PAH, EP2 expression appears to be preserved. Treprostinil is also capable of stimulating the EP3 receptor; by contrast, its downstream signaling leads to increased vascular tone. The importance of these alternative prostanoid receptors has not been fully defined.
Inhibition of Smooth Muscle Proliferation
Complex pulmonary vascular remodeling is a hallmark of PAH. Smooth muscle cell dysfunction and inappropriate growth and proliferation contribute to luminal narrowing and increased vascular resistance. In vitro, PASMCs isolated from patients with PAH demonstrate increased proliferation compared with cells from human controls. The mechanisms behind the disordered growth and remodeling are complex and incompletely understood. A significant reduction of IP on PASMCs from patients with PAH has been observed. Despite paucity of the IP receptor, treprostinil inhibits this aberrant growth in vitro; suppression was retained even with concurrent addition of a specific IP antagonist, indicating IP-independent pathways.
The work of Falcetti et al. also supports a role for peroxisome proliferator-activated receptor-γ (PPAR-γ) in smooth muscle hyperplasia in PAH. In vitro, treprostinil's antiproliferative effect on smooth muscle cells is significantly reduced with specific PPAR-γ blockade. Furthermore, growth suppression by treprostinil is potentiated by the PPAR-γ agonist rosiglitazone.
Prostacylin derivatives also participate in signaling pathways involving bone morphogenic proteins (BMPs), whose receptor BMPR-II is notably mutated in the majority of individuals with familial PAH. Stimulated BMPR-II on the surface of endothelial and smooth muscle cells affects transcription partly via inhibitors of DNA binding (Id) proteins. One antiproliferative subtype, Id1, is stimulated by prostanoids in both cell culture and the monocrotaline rat model. Thus, signaling pathways involving BMPs, BMPR-II and Ids also merit attention in discussion of the antiproliferative effects of the prostanoids.
Antiplatelet Effect
Prostacyclin and its derivatives also inhibit platelet aggregation. This action is dependent on IP; IP-knockout mice demonstrate increased platelet activation in response to vascular damage.
Stimulation of Angiogenesis
VEGF, a major stimulator of angiogenesis, is elevated in patients with idiopathic and scleroderma-related PAH. It is not clear whether upregulation of pro-angiogenesis pathways is adaptive or part of the pathogenesis of the disease; however, the prostacyclin analogs do influence signaling. Beraprost and iloprost further upregulate VEGF in vitro and in mice. Similarly, initiation of intravenous treprostinil in 13 PAH patients was associated with an increase in VEGF.
Enhancement of Inotropy
Fontana et al. observed the effect of treprostinil on isolated rat ventricular myocytes in a single study. Treprostinil alone had a minimal effect on stimulated cell shortening; however, it potentiated the positive inotropy of the β-agonist isoprenaline. The mechanism of this effect, and its applicability to other prostanoids, has not been defined.
Inhibition of Inflammation
The role of inflammatory pathways in the pathogenesis of PAH is increasingly being investigated. Patients with PAH demonstrate elevated expression of several soluble mediators, including MCP-1, IL-1β, IL-6, fractalkine and RANTES.In vitro work focusing on PAH and other inflammatory diseases demonstrates decreased production of several proinflammatory cytokines and chemokines following exposure to treprostinil and other prostanoids. Treatment of PAH patients with intravenous epoprostenol is associated with significant decrease in serum MCP-1. Interestingly, interruption of MCP-1 signaling inhibits pulmonary hypertension progression in the monocrotaline rat model. Insight into how prostacyclin may mediate MCP-1 suppression has been recently described.
While targeted inhibition of inflammation could be beneficial in limiting pathologic progression, detrimental effects of prostanoid mediated immune suppression may also be clinically important. Treprostinil inhibits both phagocytosis and subsequent bacterial killing by macrophages in vitro; stimulation of the EP2 receptor appears to be particularly important in this process. Of interest, PAH patients treated with intravenous treprostinil infusions have higher rates of bacterial bloodstream infections, and Gram-negative bloodstream infections in particular, in comparison to those on intravenous epoprostenol. In theory, this may be due to more potent immunosuppression with treprostinil; an alternative explanation, emphasizing the effect of neutral versus alkaline pH of the diluents, also has supportive data.