Patients with chronic lung diseases, particularly interstitial lung disease and chronic obstructive pulmonary disease, frequently develop pulmonary hypertension, which results in clinical deterioration, worsening of oxygen uptake, and an increased mortality risk. Pulmonary hypertension can develop and progress independently from the underlying lung disease. The pulmonary vasculopathy is distinct from that of other forms of pulmonary hypertension, with vascular ablation due to loss of small pulmonary vessels being a key feature. Long-term tobacco exposure might contribute to this type of pulmonary vascular remodelling. The distinct pathomechanisms together with the underlying lung disease might explain why treatment options for this condition remain scarce. Most drugs approved for pulmonary arterial hypertension have shown no or sometimes harmful effects in pulmonary hypertension associated with lung disease. An exception is inhaled treprostinil, which improves exercise capacity in patients with interstitial lung disease and pulmonary hypertension. There is a pressing need for safe, effective treatment options and for reliable, non-invasive diagnostic tools to detect and characterise pulmonary hypertension in patients with chronic lung disease. 

Pulmonary hypertension associated with lung disease: new insights into pathomechanisms, diagnosis, and management.

Pulmonary hypertension (PH) associated with chronic lung disease (CLD) is both common and underrecognised. The presence of PH in the setting of lung disease has been consistently shown to be associated with worse outcomes. Recent epidemiological studies have advanced understanding of the heterogeneity of this patient population and shown that defining both the specific type of CLD as well as the severity of PH ( 

Pulmonary hypertension associated with lung diseases

Given the unique physiological and pathological characteristics of the lung, the direct, inhalable route is more conducive to pulmonary drug delivery and disease control than traditional systemic drug delivery, significantly circumventing drug loss, off-target effects, systemic and organ toxicity, etc., and is widely regarded as the preferred regimen for pulmonary drug delivery. However, very few lung diseases are currently treated with the preferred inhaled formulations, such as asthma, chronic obstructive pulmonary disease and pulmonary hypertension. And there is a lack of appropriate inhaled formulations for other critical lung diseases, such as lung cancer and pulmonary fibrosis, due to the fact that the physicochemical properties of the drugs and their pharmacokinetic profiles do not match the physiology of the lung, and conventional inhalation devices are unable to deliver them to the specific parts of the lung. Phytochemicals of natural origin, due to their wide availability and clear safety profile, hold great promise for the preparation of inhalable formulations to improve the current dilemma in the treatment of lung diseases. In particular, the preparation of inhalable formulations based on nano- and microparticulate carriers for drug delivery to deep lung tissues, which overcome the shortcomings of conventional inhalation therapies while targeting the drug activity directly to a specific part of the lung, may be the best approach to change the current dilemma of lung disease treatment. In this review, we discuss recent advances in nano- and micron-carrier-based inhalation formulations for the delivery of natural products for the treatment of pulmonary diseases, which may represent an opportunity for practical clinical translation of natural products. 

Natural Products-Based Inhaled Formulations for Treating Pulmonary Diseases

Pulmonary hypertension (PH) associated with interstitial lung disease (ILD-PH) is classified as group 3 PH, i.e. PH associated with chronic lung disease and/or hypoxia [1]. PH is relatively frequent in patients with ILD, depending on the definition of PH, the diagnostic assessment of PH, and the type of underlying ILD [2]. In patients with idiopathic pulmonary fibrosis (IPF), PH is a frequent complication at an advanced stage of the disease [3], or when emphysema is associated, as in the syndrome of combined pulmonary fibrosis and emphysema [4, 5]. Tweetable abstract Pulmonary hypertension associated with ILD is a very severe condition. The open label extension of the INCREASE trial demonstrates acceptable tolerability of inhaled treprostinil, maintained exercise capacity at week 40, and increase in FVC. https://bit.ly/3qxHvsB

Inhaled treprostinil for interstitial lung disease-associated pulmonary hypertension: a silver lining on a very dark cloud

The prostacyclin (PGI2) receptor (IP) is a Gs-coupled receptor associated with blood pressure regulation, allergy, and inflammatory response. It is a main therapeutic target for pulmonary arterial hypertension (PAH) and several other diseases. Here we report cryo–electron microscopy (cryo-EM) structures of the human IP-Gs complex bound with two anti-PAH drugs, treprostinil and MRE-269 (active form of selexipag), at global resolutions of 2.56 and 2.41 angstrom, respectively. These structures revealed distinct features governing IP ligand binding, receptor activation, and G protein coupling. Moreover, comparison of the activated IP structures uncovered the mechanism and key residues that determine the superior selectivity of MRE-269 over treprostinil. Combined with molecular docking and functional studies, our structures provide insight into agonist selectivity, ligand recognition, receptor activation, and G protein coupling. Our results provide a structural template for further improving IP-targeting drugs to reduce off-target activation of prostanoid receptors and adverse effects.

Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs

Introduction The 16-week randomised, placebo-controlled INCREASE trial (RCT) met its primary end-point by improving 6-min walk distance (6MWD) in patients receiving inhaled treprostinil for pulmonary hypertension due to interstitial lung disease (PH-ILD). The open-label extension (OLE) evaluated long-term effects of inhaled treprostinil in PH-ILD. Methods Of 258 eligible patients, 242 enrolled in the INCREASE OLE and received inhaled treprostinil. Assessments included 6MWD, pulmonary function testing, N-terminal pro-brain natriuretic peptide (NT-proBNP), quality of life and adverse events. Hospitalisations, exacerbations of underlying lung disease and death were recorded. Results At INCREASE OLE baseline, patients had a median age of 70 years and a mean 6MWD of 274.2 m; 52.1% were male. For the overall population, the mean 6MWD at week 52 was 279.1 m and the mean change from INCREASE RCT baseline was 3.5 m (22.1 m for the prior inhaled treprostinil arm and −19.5 m for the prior placebo arm); the median NT-proBNP decreased from 389 pg·mL−1 at RCT baseline to 359 pg·mL−1 at week 64; and the absolute (% predicted) mean forced vital capacity change from RCT baseline to week 64 was 51 mL (2.8%). Patients who received inhaled treprostinil versus placebo in the RCT had a 31% lower relative risk of exacerbation of underlying lung disease in the OLE (hazard ratio 0.69 (95% CI 0.49–0.97); p=0.03). Adverse events leading to drug discontinuation occurred in 54 (22.3%) patients. Conclusions These results support the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD, and are consistent with the results observed in the INCREASE RCT. The INCREASE open-label extension supports the safety and efficacy of long-term treatment with inhaled treprostinil in patients with interstitial lung disease and associated pulmonary hypertension http://bit.ly/3KiEClA

https://erj.ersjournals.com/content/erj/early/2023/03/29/13993003.02414-2022.full.pdf

Long-term inhaled treprostinil for pulmonary hypertension due to interstitial lung disease: INCREASE open-label extension study

INTRODUCTION
The 16-week randomised, placebo-controlled INCREASE trial (RCT) met its primary endpoint by improving 6-minute walk distance (6MWD) in patients receiving inhaled treprostinil for pulmonary hypertension due to interstitial lung disease (PH-ILD). The open-label extension (OLE) evaluated long-term effects of inhaled treprostinil in PH-ILD.


METHODS
Of 258 eligible patients, 242 enrolled in the OLE and received inhaled treprostinil. Assessments included 6MWD, pulmonary function testing, N-terminal pro-brain natriuretic peptide (NT-proBNP), quality of life, and adverse events. Hospitalizations, exacerbations of underlying lung disease, and death were recorded.


RESULTS
At OLE baseline, patients had a median age of 70 years and a mean 6MWD of 274.2 m; 52.1% were male. For the overall population, the mean 6MWD at week 52 was 279.1 m and the median change from RCT baseline was 3.5 m (22.1 m for the prior inhaled treprostinil arm, -19.5 m for the prior placebo arm); the median NT-proBNP decreased from 389 pg·mL-1 at RCT baseline to 359 pg·mL-1 at week 64; and the absolute (% predicted) mean FVC change from RCT baseline to week 64 was 51 mL (2.8%). Patients who received inhaled treprostinil versus placebo in the RCT had a 31% lower relative risk of exacerbation of underlying lung disease in the OLE (hazard ratio=0.69 [95% confidence interval: 0.49-0.97]; p=0.03). Adverse events leading to drug discontinuation occurred in 54 (22.3%) patients.


CONCLUSION
These results support the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD and are consistent with the results observed in the INCREASE RCT.

/pdf/long-term-inhaled-treprostinil-for-ph-ild-increase-open-1evop1d7.pdf

Long-term inhaled treprostinil for PH-ILD: INCREASE open-label extension study.

Deupirfenidone Compared to Placebo and Pirfenidone in Idiopathic Pulmonary Fibrosis: ELEVATE IPF Phase 2b Trial

Factors Associated With Persistence With Antifibrotic Therapy in Patients With Idiopathic Pulmonary Fibrosis Enrolled in the Pulmonary Fibrosis Foundation Patient Registry

Clarifying the Pathway to an Accurate Diagnosis of Interstitial Lung Disease: Results from a Modified Delphi Survey in the US

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