PMID- 35841089
OWN - NLM
STAT- MEDLINE
DCOM- 20220719
LR  - 20220719
IS  - 1465-993X (Electronic)
IS  - 1465-9921 (Print)
IS  - 1465-9921 (Linking)
VI  - 23
IP  - 1
DP  - 2022 Jul 15
TI  - Platelet-derived growth factor (PDGF)-BB regulates the airway tone via activation 
      of MAP2K, thromboxane, actin polymerisation and Ca(2+)-sensitisation.
PG  - 189
LID - 10.1186/s12931-022-02101-x [doi]
LID - 189
AB  - BACKGROUND: PDGFR-inhibition by the tyrosine kinase inhibitor (TKI) nintedanib 
      attenuates the progress of idiopathic pulmonary fibrosis (IPF). However, the 
      effects of PDGF-BB on the airway tone are almost unknown. We studied this issue 
      and the mechanisms beyond, using isolated perfused lungs (IPL) of guinea pigs 
      (GPs) and precision-cut lung slices (PCLS) of GPs and humans. METHODS: IPL: 
      PDGF-BB was perfused after or without pre-treatment with the TKI imatinib 
      (perfused/nebulised) and its effects on the tidal volume (TV), the dynamic 
      compliance (Cdyn) and the resistance were studied. PCLS (GP): The 
      bronchoconstrictive effects of PDGF-BB and the mechanisms beyond were evaluated. 
      PCLS (human): The bronchoconstrictive effects of PDGF-BB and the bronchorelaxant 
      effects of imatinib were studied. All changes of the airway tone were measured by 
      videomicroscopy and indicated as changes of the initial airway area. RESULTS: 
      PCLS (GP/human): PDGF-BB lead to a contraction of airways. IPL: PDGF-BB decreased 
      TV and Cdyn, whereas the resistance did not increase significantly. In both 
      models, inhibition of PDGFR-(beta) (imatinib/SU6668) prevented the 
      bronchoconstrictive effect of PDGF-BB. The mechanisms beyond PDGF-BB-induced 
      bronchoconstriction include activation of MAP2K and TP-receptors, actin 
      polymerisation and Ca(2+)-sensitisation, whereas the increase of Ca(2+) itself 
      and the activation of EP(1-4)-receptors were not of relevance. In addition, 
      imatinib relaxed pre-constricted human airways. CONCLUSIONS: PDGFR regulates the 
      airway tone. In PCLS from GPs, this regulatory mechanism depends on the 
      beta-subunit. Hence, PDGFR-inhibition may not only represent a target to improve 
      chronic airway disease such as IPF, but may also provide acute bronchodilation in 
      asthma. Since asthma therapy uses topical application. This is even more 
      relevant, as nebulisation of imatinib also appears to be effective.
CI  - (c) 2022. The Author(s).
FAU - Rieg, Annette D
AU  - Rieg AD
AUID- ORCID: 0000-0002-7043-5494
AD  - Department of Anaesthesiology, Medical Faculty RWTH-Aachen, Aachen, Germany. 
      arieg@ukaachen.de.
FAU - Suleiman, Said
AU  - Suleiman S
AD  - Institute of Pharmacology and Toxicology, Medical Faculty RWTH-Aachen, Aachen, 
      Germany.
FAU - Anker, Carolin
AU  - Anker C
AD  - Institute of Pharmacology and Toxicology, Medical Faculty RWTH-Aachen, Aachen, 
      Germany.
FAU - Bunting, Nina A
AU  - Bunting NA
AD  - Institute of Pharmacology and Toxicology, Medical Faculty RWTH-Aachen, Aachen, 
      Germany.
FAU - Verjans, Eva
AU  - Verjans E
AD  - Department of Paediatrics, Medical Faculty RWTH-Aachen, Aachen, Germany.
FAU - Spillner, Jan
AU  - Spillner J
AD  - Department of Cardiac and Thorax Surgery, Medical Faculty RWTH-Aachen, Aachen, 
      Germany.
FAU - Kalverkamp, Sebastian
AU  - Kalverkamp S
AD  - Department of Cardiac and Thorax Surgery, Medical Faculty RWTH-Aachen, Aachen, 
      Germany.
FAU - von Stillfried, Saskia
AU  - von Stillfried S
AD  - Institute of Pathology, Medical Faculty RWTH-Aachen, Aachen, Germany.
FAU - Braunschweig, Till
AU  - Braunschweig T
AD  - Institute of Pathology, Medical Faculty RWTH-Aachen, Aachen, Germany.
FAU - Uhlig, Stefan
AU  - Uhlig S
AD  - Institute of Pharmacology and Toxicology, Medical Faculty RWTH-Aachen, Aachen, 
      Germany.
FAU - Martin, Christian
AU  - Martin C
AD  - Institute of Pharmacology and Toxicology, Medical Faculty RWTH-Aachen, Aachen, 
      Germany.
LA  - eng
PT  - Journal Article
DEP - 20220715
PL  - England
TA  - Respir Res
JT  - Respiratory research
JID - 101090633
RN  - 0 (Actins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-sis)
RN  - 0 (Thromboxanes)
RN  - 1B56C968OA (Becaplermin)
RN  - 25X51I8RD4 (Niacinamide)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - *Actins
MH  - Animals
MH  - *Asthma
MH  - Becaplermin
MH  - Guinea Pigs
MH  - Humans
MH  - Imatinib Mesylate/pharmacology
MH  - Mitogen-Activated Protein Kinase Kinases
MH  - Niacinamide
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-sis
MH  - Receptor, Platelet-Derived Growth Factor beta/metabolism
MH  - Thromboxanes
PMC - PMC9287894
COIS- The authors declare that they have no competing interests.
EDAT- 2022/07/16 06:00
MHDA- 2022/07/20 06:00
PMCR- 2022/07/15
CRDT- 2022/07/15 23:49
PHST- 2021/05/01 00:00 [received]
PHST- 2022/06/30 00:00 [accepted]
PHST- 2022/07/15 23:49 [entrez]
PHST- 2022/07/16 06:00 [pubmed]
PHST- 2022/07/20 06:00 [medline]
PHST- 2022/07/15 00:00 [pmc-release]
AID - 10.1186/s12931-022-02101-x [pii]
AID - 2101 [pii]
AID - 10.1186/s12931-022-02101-x [doi]
PST - epublish
SO  - Respir Res. 2022 Jul 15;23(1):189. doi: 10.1186/s12931-022-02101-x.