Orotracheal treprostinil administration attenuates bleomycin‐induced lung injury, vascular remodeling, and fibrosis in mice

Abstract

Pulmonary fibrosis is a progressive disease characterized by disruption of lung architecture and deregulation of the pulmonary function. Prostacyclin, a metabolite of arachidonic acid, is a potential disease mediator since it exerts anti-inflammatory and anti-fibrotic actions. We investigated the effect of treprostinil, a prostacyclin analogue, in bleomycin-induced experimental pulmonary fibrosis. Bleomycin sulfate or saline was administrated intratracheally to mice ( n = 9–10/group) at day 0. Orotracheal aspiration of treprostinil or vehicle was administered daily and started 24 h prior to bleomycin challenge. Evaluation of lung pathology was performed in tissue samples and bronchoalveolar lavage fluid collected 7, 14 and 21 days after bleomycin exposure. Lung injury was achieved due to bleomycin exposure at all time points as indicated by impaired lung mechanics, pathologic lung architecture (from day 14), and cellular and protein accumulation in the alveolar space accompanied by a minor decrease in lung tissue VE-cadherin at day 14. Treprostinil preserved lung mechanics, and reduced lung inflammation, fibrosis, and vascular remodeling (day 21); reduced cellularity and protein content of bronchoalveolar lavage fluid were additionally observed with no significant effect on VE-cadherin expression. Bleomycin-induced collagen deposition was attenuated by treprostinil from day 14, while treprostinil involvement in regulating inflammatory processes appears mediated by NF-κB signaling. Overall, prophylactic administration of treprostinil, a stable prostacyclin analogue, maintained lung function, and prevented bleomycin-induced lung injury, and fibrosis, as well as vascular remodeling, a hallmark of pulmonary hypertension. This suggests potential therapeutic efficacy of treprostinil in pulmonary fibrosis and possibly in pulmonary hypertension related to chronic lung diseases.

International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2Receptors (EP1–4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions

“…A similar protective effect was found in rats submitted to inhalation of nanoparticle INS1009 containing treprostinil (IP agonist) prodrug (C16TR), which inhibited bleomycin-induced pulmonary fibrosis ( Corboz et al, 2018 ). In other studies, iloprost and treprostinil protected against bleomycin-induced pulmonary fibrosis ( Zhu et al, 2011 ; Nikitopoulou et al, 2019 ). In both studies, mice treated with bleomycin+iloprost showed a normal alveolar structure and reduced lung inflammation compared with those treated with bleomycin alone, with lower proinflammatory cytokine (TNF- α , IL-6, TGF- β 1) concentrations in broncho-alveolar lavage reported in the former study and reduced inflammatory cell infiltration in the latter.…”

Exosomes derived from three-dimensional cultured human umbilical cord mesenchymal stem cells ameliorate pulmonary fibrosis in a mouse silicosis model

“…We carried out lung function measurements to further evaluate the changes of pulmonary function-in silica-induced PF in mice, along with the protective effects of hucMSC-Exos by FOT measurements objectively. FOT measurements are an invasive method that can measure relevant parameters physiologically and describe the mechanical properties of the respiratory system accurately, which have been used to explore pathophysiological changes associated with fibrosis in mice models of respiratory diseases [ 29 , 30 ]. The classical parameters of respiratory mechanics, resistance, and compliance are related to the resistance of air in and out of the lungs as well as the expandability of the respiratory system.…”

Strategies to Overcome Biological Barriers Associated with Pulmonary Drug Delivery

“…Treatment for pulmonary fibrosis typically involves administration of either oral pirfenidone (a pyridine with anti-fibrotic activity) or nintedanib (tyrosine kinase inhibitor), oxygen therapy, pulmonary rehabilitation, or in some instances lung transplant [112]. Recently, prostacyclin analogs [103,113] and phosphoinositide 3-kinase (PI3K) pan inhibitors [114,115] have shown promise in models of PF with examples of both classes of drugs being evaluated via the inhaled route of administration.…”