PMID- 35927669
OWN - NLM
STAT- MEDLINE
DCOM- 20220808
LR  - 20220808
IS  - 1465-993X (Electronic)
IS  - 1465-9921 (Print)
IS  - 1465-9921 (Linking)
VI  - 23
IP  - 1
DP  - 2022 Aug 4
TI  - Nintedanib modulates type III collagen turnover in viable precision-cut lung 
      slices from bleomycin-treated rats and patients with pulmonary fibrosis.
PG  - 201
LID - 10.1186/s12931-022-02116-4 [doi]
LID - 201
AB  - BACKGROUND: Aberrant extracellular matrix (ECM) deposition and remodelling is 
      important in the disease pathogenesis of pulmonary fibrosis (PF). We 
      characterised neoepitope biomarkers released by ECM turnover in lung tissue from 
      bleomycin-treated rats and patients with PF and analysed the effects of two 
      antifibrotic drugs: nintedanib and pirfenidone. METHODS: Precision-cut lung 
      slices (PCLS) were prepared from bleomycin-treated rats or patients with PF. PCLS 
      were incubated with nintedanib or pirfenidone for 48 h, and levels of neoepitope 
      biomarkers of type I, III and VI collagen formation or degradation (PRO-C1, 
      PRO-C3, PRO-C6 and C3M) as well as fibronectin (FBN-C) were assessed in the 
      culture supernatants. RESULTS: In rat PCLS, incubation with nintedanib led to a 
      reduction in C3M, reflecting type III collagen degradation. In patient PCLS, 
      incubation with nintedanib reduced the levels of PRO-C3 and C3M, thus showing 
      effects on both formation and degradation of type III collagen. Incubation with 
      pirfenidone had a marginal effect on PRO-C3. There were no other notable effects 
      of either nintedanib or pirfenidone on the other neoepitope biomarkers studied. 
      CONCLUSIONS: This study demonstrated that nintedanib modulates neoepitope 
      biomarkers of type III collagen turnover and indicated that C3M is a promising 
      translational neoepitope biomarker of PF in terms of therapy assessment.
CI  - (c) 2022. The Author(s).
FAU - Hesse, Christina
AU  - Hesse C
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Member of 
      German Center for Lung Research (DZL), Hannover, Germany.
AD  - Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), 
      Member of Fraunhofer International Consortium for Anti-Infective Research 
      (iCAIR), Member of Fraunhofer Cluster of Excellence Immune-Mediated Diseases 
      (CIMD), Hannover, Germany.
FAU - Beneke, Valerie
AU  - Beneke V
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Member of 
      German Center for Lung Research (DZL), Hannover, Germany.
AD  - Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), 
      Member of Fraunhofer International Consortium for Anti-Infective Research 
      (iCAIR), Member of Fraunhofer Cluster of Excellence Immune-Mediated Diseases 
      (CIMD), Hannover, Germany.
FAU - Konzok, Sebastian
AU  - Konzok S
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Member of 
      German Center for Lung Research (DZL), Hannover, Germany.
AD  - Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), 
      Member of Fraunhofer International Consortium for Anti-Infective Research 
      (iCAIR), Member of Fraunhofer Cluster of Excellence Immune-Mediated Diseases 
      (CIMD), Hannover, Germany.
FAU - Diefenbach, Claudia
AU  - Diefenbach C
AD  - Translational Medicine + Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH 
      & Co. KG, Biberach, Germany.
FAU - Bulow Sand, Jannie Marie
AU  - Bulow Sand JM
AD  - Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark.
FAU - Ronnow, Sarah Rank
AU  - Ronnow SR
AD  - Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark.
FAU - Karsdal, Morten Asser
AU  - Karsdal MA
AD  - Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark.
FAU - Jonigk, Danny
AU  - Jonigk D
AD  - Institute of Pathology, Hannover Medical School, Hannover, Germany.
AD  - Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), 
      Member of German Center for Lung Research (DZL), Hannover, Germany.
FAU - Sewald, Katherina
AU  - Sewald K
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Member of 
      German Center for Lung Research (DZL), Hannover, Germany.
AD  - Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), 
      Member of Fraunhofer International Consortium for Anti-Infective Research 
      (iCAIR), Member of Fraunhofer Cluster of Excellence Immune-Mediated Diseases 
      (CIMD), Hannover, Germany.
FAU - Braun, Armin
AU  - Braun A
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Member of 
      German Center for Lung Research (DZL), Hannover, Germany.
AD  - Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), 
      Member of Fraunhofer International Consortium for Anti-Infective Research 
      (iCAIR), Member of Fraunhofer Cluster of Excellence Immune-Mediated Diseases 
      (CIMD), Hannover, Germany.
FAU - Leeming, Diana Julie
AU  - Leeming DJ
AD  - Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark.
FAU - Wollin, Lutz
AU  - Wollin L
AUID- ORCID: 0000-0002-3617-5772
AD  - Translational Medicine + Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH 
      & Co. KG, Biberach, Germany. stefan-lutz.wollin@boehringer-ingelheim.com.
LA  - eng
PT  - Journal Article
DEP - 20220804
PL  - England
TA  - Respir Res
JT  - Respiratory research
JID - 101090633
RN  - 0 (Biomarkers)
RN  - 0 (Collagen Type III)
RN  - 0 (Complement C3)
RN  - 0 (Indoles)
RN  - 11056-06-7 (Bleomycin)
RN  - G6HRD2P839 (nintedanib)
SB  - IM
MH  - Animals
MH  - Biomarkers
MH  - Bleomycin/toxicity
MH  - Collagen Type III/metabolism
MH  - Complement C3/pharmacology
MH  - *Idiopathic Pulmonary Fibrosis/chemically induced/drug therapy/pathology
MH  - Indoles
MH  - Lung/metabolism
MH  - *Pulmonary Fibrosis/chemically induced/drug therapy/pathology
MH  - Rats
PMC - PMC9351157
OTO - NOTNLM
OT  - Antifibrotic therapy
OT  - Collagen
OT  - Extracellular matrix
OT  - Human lung
OT  - Neoepitope biomarkers
OT  - Nintedanib
OT  - Pirfenidone
OT  - Precision-cut lung slices
OT  - Pulmonary fibrosis
COIS- CH, VB, SK, DJ, KS and AB have nothing to declare. CD and LW are employees of 
      Boehringer Ingelheim, the marketing authorisation holder of nintedanib used in 
      this study. JMBS, SRR, MAK and DJL are full-time employees and stock owners at 
      Nordic Bioscience. JMBS holds patent PRO-C6 assay (US20190309055A1; 
      US20180088129A1). MAK is a patent- holder for assays for C1M (ref. 9359633 [US]), 
      C3M (ref. 9359633 [US]) and PRO-C3 (ref. 9726674 [US]). DJL is a patent- holder 
      for assays for this manuscript. Fraunhofer ITEM is a public, non-profit research 
      organization who perform contract research on behalf of the pharmaceutical and 
      biotech industry.
EDAT- 2022/08/05 06:00
MHDA- 2022/08/09 06:00
PMCR- 2022/08/04
CRDT- 2022/08/04 23:45
PHST- 2021/11/26 00:00 [received]
PHST- 2022/07/21 00:00 [accepted]
PHST- 2022/08/04 23:45 [entrez]
PHST- 2022/08/05 06:00 [pubmed]
PHST- 2022/08/09 06:00 [medline]
PHST- 2022/08/04 00:00 [pmc-release]
AID - 10.1186/s12931-022-02116-4 [pii]
AID - 2116 [pii]
AID - 10.1186/s12931-022-02116-4 [doi]
PST - epublish
SO  - Respir Res. 2022 Aug 4;23(1):201. doi: 10.1186/s12931-022-02116-4.