Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease

Waxman, Aaron B.; Restrepo‐Jaramillo, Ricardo; Thenappan, Thenappan; Ravichandran, Ashwin; Engel, Peter J.; Bajwa, Abubakr; Allen, Roblee P.; Feldman, Jeremy; Argula, Rahul; Smith, Peter; Rollins, Kristan; Deng, Chunqin; Peterson, Leigh; Bell, Heidi; Tapson, Victor F.; Nathan, Steven D.

doi:10.1056/nejmoa2008470

Cited by 368 publications

(414 citation statements)

References 16 publications

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“…57 Nevertheless, as this was not a prospective, controlled trial, the effects of parenteral prostacyclin in patients with PH/PF reported here do not prove efficacy of this agent, although recent data using inhaled prostacyclin appear promising in PH/PF and importantly, included an AI subgroup. 58 AI and younger age at PH diagnosis were independently associated with improved transplant-free survival. While younger age also predicts better survival in Group I PAH, 59,60 AI associated with Group 1 PAH actually portends a poorer survival when compared to idiopathic PAH, despite similar hemodynamic responses to PAH-specific therapy.…”

Section: Discussionmentioning

confidence: 90%

Significance of autoimmune disease in severe pulmonary hypertension complicating extensive pulmonary fibrosis: a prospective cohort study

Saggar¹,

Giri

Deng

et al. 2021

Pulm. circ.

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Background: The association of autoimmune disease (AI) with transplant-free survival in the setting of severe Group 3 Pulmonary Hypertension (PH) and extensive Pulmonary Fibrosis (PF) remains unclear. Methods: We report cases of severe PH [mean pulmonary artery pressure (mPAP) >35mmHg and right ventricular (RV) dysfunction] and extensive PF after pulmonary arterial hypertension (PAH)-specific therapy. We used multivariate regression to determine the clinical variables associated with transplant-free survival. Results: Of 286 screened patients, 55 demonstrated severe PH and extensive PF and were treated with parenteral prostacyclin therapy. The (+)AI subgroup (n=34), when compared to the (-)AI subgroup (n=21), was more likely to be female (77% versus 19%) and younger (58.7+12.1 versus 66.0+10.7 years), and revealed lower FVC [absolute] (1.9+0.7 versus 2.9+1.1 liters), higher DLCO [% predicted] (31.1+15.2 versus 23.2+8.0), and increased unadjusted transplant-free survival [1 year (84.6+6.3% versus 45+11.1%), 3 year (71+8.2% versus 28.6+11.9%), and 5 year (47.6+9.6% versus 6.4+8.2%); (p=0.01)]. Transplant-free survival was unchanged after adjusting for age and gender. The pulmonary hemodynamic profiles improved after parenteral prostacyclin therapy, independent of AI status. The baseline variables associated with mortality included age at PH diagnosis (HR 1.23 [CI 1.03-1.47]; p=0.02) and presence of AI (HR 0.26 [CI 0.10-0.70]; p<0.01). Gas exchange was not adversely affected by parenteral prostacyclin therapy. Conclusions: In the setting of severe Group 3 PH and extensive PF treated with PAH-specific therapy, AI is independently associated with increased transplant-free survival. PH/PF associated with AI should be considered in future clinical trials of PAH-specific therapy in Group 3 PH.

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Section: Discussionmentioning

confidence: 90%

Significance of autoimmune disease in severe pulmonary hypertension complicating extensive pulmonary fibrosis: a prospective cohort study

Saggar¹,

Giri

Deng

et al. 2021

Pulm. circ.

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“…Our studies do leave several mechanistic questions unanswered. Recently, the cAMP agonist treprostinil, in a phase 2 study of patients with interstitial lung disease (ILD) and pulmonary hypertension, was associated with improved exercise based on 6-minute walk test when compared to placebo (64). We have observed that CXCL6-induced collagen is independent of treprostinil and by extension, independent of cAMP.…”

Section: Discussionmentioning

confidence: 97%

High CXCL6 drives matrix expression and correlate with markers of poor outcome in IPF

Bahudhanapati

Tan

Apel

et al. 2021

Preprint

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Signaling via G protein-coupled receptors (GPCRs) can modulate levels of cyclic adenosine monophosphate (cAMP) and shape the functions of fibroblasts in idiopathic pulmonary fibrosis (IPF). We have identified Chemokine (C-X-C) Motif Ligand 6 (CXCL6) as a potential pro-fibrotic GPCR ligand. We tested the function of CXCL6 in ex vivo human donor and fibrotic lung fibroblasts and in an animal model of pulmonary fibrosis. We also measured levels of CXCL6 in the blood and bronchoalveolar lavage (BAL) of patients with IPF. CXCL6 decreased cAMP levels in a dose-dependent manner in Donor and IPF Fibroblasts. CXCL6 mRNA and protein were localized to epithelial cells. Administration of mCXCL5 (LIX, murine CXCL6 homologue) to mice increased collagen synthesis with and without bleomycin. CXCL6 increased Collagen I and α-SMA levels in Donor and IPF Fibroblasts. Silencing of CXCR1/2 as well as Reparixin, a CXCR1/2 inhibitor, blocked effects of CXCL6. Treprostinil blocked effects of CXCL6 only on levels of α-SMA but not on Collagen I. CXCL6 levels in the BAL of two separate cohorts of patients with IPF was associated with poor survival. We conclude that high CXCL6 drives fibroblast function and correlates with poor outcomes in IPF.

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“…More robust tools have been used to improve the oral bioavailability of therapeutic peptides, e.g., oral application of insulin-polyarginine conjugates ( Morishita et al, 2007 ). Inhalable peptides were also used with promising results in treating pulmonary and systemic diseases ( Greene et al, 2020 ; Waxman et al, 2021 ). These technologies offer a promising future for peptide drug development.…”

Section: Discussionmentioning

confidence: 99%

Discovery of New Potent anti-MERS CoV Fusion Inhibitors

et al. 2021

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Middle East respiratory syndrome coronavirus (MERS-CoV), capable of zoonotic transmission, has been associated with emerging viral pneumonia in humans. In this study, a set of highly potent peptides were designed to prevent MERS-CoV fusion through competition with heptad repeat domain 2 (HR2) at its HR1 binding site. We designed eleven peptides with stronger estimated HR1 binding affinities than the wild-type peptide to prevent viral fusion with the cell membrane. Eight peptides showed strong inhibition of spike-mediated MERS-CoV cell-cell fusion with IC50 values in the nanomolar range (0.25–2.3 µM). Peptides #4–6 inhibited 95–98.3% of MERS-CoV plaque formation. Notably, peptide four showed strong inhibition of MERS-CoV plaques formation with EC50 = 0.302 µM. All peptides demonstrated safe profiles without cytotoxicity up to a concentration of 10 μM, and this cellular safety, combined with their anti-MERS-CoV antiviral activity, indicate all peptides can be regarded as potential promising antiviral agents.

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Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease

Cited by 368 publications

References 16 publications

Significance of autoimmune disease in severe pulmonary hypertension complicating extensive pulmonary fibrosis: a prospective cohort study

Significance of autoimmune disease in severe pulmonary hypertension complicating extensive pulmonary fibrosis: a prospective cohort study

High CXCL6 drives matrix expression and correlate with markers of poor outcome in IPF

Discovery of New Potent anti-MERS CoV Fusion Inhibitors

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