Pharmacological Treatment of Interstitial Lung Diseases: A Novel Landscape for Inhaled Agents

Abstract

Interstitial lung diseases (ILDs) encompass a heterogeneous group of over 200 disorders that require individualized treatment. Antifibrotic agents, such as nintedanib and pirfenidone, have remarkably revolutionized the treatment landscape of patients with idiopathic pulmonary fibrosis (IPF). Moreover, the approval of nintedanib has also expanded the therapeutic options for patients with progressive pulmonary fibrosis other than IPF. However, despite recent advances, current therapeutic strategies based on antifibrotic agents and/or immunomodulation are associated with non-negligible side effects. Therefore, several studies have explored the inhalation route aiming to spread higher local concentrations while limiting systemic toxicity. In this review, we examined the currently available literature about preclinical and clinical studies testing the efficacy and safety of inhalation-based antifibrotics, immunomodulatory agents, antioxidants, mucolytics, bronchodilators, and vasodilator agents in ILDs.

Keywords: antifibrotics; antioxidants; bronchodilators; corticosteroids; idiopathic pulmonary fibrosis; inhaled agents; interstitial lung diseases.

Figure 1

Inhaling molecules under investigation in pulmonary fibrosis treatment. Smoking, air pollution, and dust represent the main noxae involved in ROS production and inflammation ignited within the lungs. This eventually may lead to a sustained aberrant response of alveolar epithelial cells leading EMT to progress and, finally, to fibrosis and lung parenchyma destruction. Several inhaling molecules are currently under investigation for future employment in pulmonary fibrosis treatment. *: PLGA–nintedanib has currently only been tested in vitro, by Wang et al. [36]. α-SMA: alpha-smooth muscle actin; DMF: dimethyl fumarate; Gal-3: galectin 3; Gly: glycine; EMT: epithelial–mesenchymal transition; HO-1: heme oxygenase 1; Leu: leucine; Lip@VP: Liposome@verteporfin/pirfenidone; LUT@CDMOFs: Luteolin into γ-cyclodextrin metal–organic frameworks; MMP-9: matrix metalloproteinase-9; NAC: N-acetyl cysteine; NF-κB: nuclear factor kappa B; NLRP3: NLR family pyrin domain-containing 3; Nrf2: nuclear factor erythroid factor 2-related factor 2; NS: nanosuspension; PI3Ks: phosphoinositide 3-kinases; PKB: protein kinase B; PLGA: poly lactic-co-glycolic acid; ROS: reactive oxygen species; TD139: thiodigalactoside galectin-3 inhibitor; TGF-β1: transforming growth factor beta 1.