Evaluation of Pirfenidone and Nintedanib in a Human Lung Model of Fibrogenesis

Copyright © 2021 Roach, Castells, Dixon, Mason, Elliott, Marshall, Poblocka, Macip, Richardson, Khalfaoui and Bradding..

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Pirfenidone and nintedanib are the only approved treatments for IPF but have limited efficacy and their mechanisms of action are poorly understood. Here we have examined the effects of pirfenidone and nintedanib in a human model of lung fibrogenesis, and compared these with the putative anti-fibrotic compounds Lipoxin A4 (LXA4), and senicapoc, a KCa3.1 ion channel blocker. Methods: Early fibrosis was induced in cultured human lung parenchyma using TGFβ1 for 7 days, ± pirfenidone, nintedanib, or LXA4. Pro-fibrotic responses were examined by RT-PCR, immunohistochemistry and soluble collagen secretion. Results: Thirty six out of eighty four IPF and fibrosis-associated genes tested were significantly upregulated by TGFβ1 in human lung parenchyma with a ≥0.5 log2FC (n = 32). Nintedanib (n = 13) reduced the mRNA expression of 14 fibrosis-associated genes including MMPs (MMP1,-4,-13,-14), integrin α2, CXCR4 and PDGFB, but upregulated α-smooth muscle actin (αSMA). Pirfenidone only reduced mRNA expression for MMP3 and -13. Senicapoc (n = 11) previously attenuated the expression of 28 fibrosis-associated genes, including αSMA, several growth factors, collagen type III, and αV/β6 integrins. Pirfenidone and nintedanib significantly inhibited TGFβ1-induced fibroblast proliferation within the tissue, but unlike senicapoc, neither pirfenidone nor nintedanib prevented increases in tissue αSMA expression. LXA4 was ineffective. Conclusions: Pirfenidone and nintedanib demonstrate modest anti-fibrotic effects and provide a benchmark for anti-fibrotic activity of new drugs in human lung tissue. Based on these data, we predict that the KCa3.1 blocker senicapoc will show greater benefit than either of these licensed drugs in IPF.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:12

Enthalten in:

Frontiers in pharmacology - 12(2021) vom: 19., Seite 679388

Sprache:

Englisch

Beteiligte Personen:

Roach, K M [VerfasserIn]
Castells, E [VerfasserIn]
Dixon, K [VerfasserIn]
Mason, S [VerfasserIn]
Elliott, G [VerfasserIn]
Marshall, H [VerfasserIn]
Poblocka, M A [VerfasserIn]
Macip, S [VerfasserIn]
Richardson, M [VerfasserIn]
Khalfaoui, L [VerfasserIn]
Bradding, P [VerfasserIn]

Links:

Volltext

Themen:

Fibrosis
Human model
IPF
Journal Article
KCa3.1
Lung
Nintedanib
Pirfenidone
Senicapoc

Anmerkungen:

Date Revised 15.03.2023

published: Electronic-eCollection

Citation Status PubMed-not-MEDLINE

doi:

10.3389/fphar.2021.679388

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM332504425