PMID- 37658546
OWN - NLM
STAT- Publisher
LR  - 20230926
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Linking)
DP  - 2023 Sep 1
TI  - The small-molecule formyl peptide receptor biased agonist, compound 17b, is a 
      vasodilator and anti-inflammatory in mouse precision-cut lung slices.
LID - 10.1111/bph.16231 [doi]
AB  - BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH), a rare fatal 
      disorder characterised by inflammation, vascular remodelling and 
      vasoconstriction. Current vasodilator therapies reduce pulmonary arterial 
      pressure but not mortality. The G-protein coupled formyl peptide receptors (FPRs) 
      mediates vasodilatation and resolution of inflammation, actions possibly 
      beneficial in PAH. We investigated dilator and anti-inflammatory effects of the 
      FPR biased agonist compound 17b in pulmonary vasculature using mouse 
      precision-cut lung slices (PCLS). EXPERIMENTAL APPROACH: PCLS from 8-week-old 
      male and female C57BL/6 mice, intrapulmonary arteries were pre-contracted with 
      5-HT for concentration-response curves to compound 17b and 43, and 
      standard-of-care drugs, sildenafil, iloprost and riociguat. Compound 17b-mediated 
      relaxation was assessed with FPR antagonists or inhibitors and in PCLS treated 
      with TNF-alpha or LPS. Cytokine release from TNF-alpha- or LPS-treated PCLS +/- compound 
      17b was measured. KEY RESULTS: Compound 17b elicited concentration-dependent 
      vasodilation, with potencies of iloprost > compound 17b = riociguat > compound 
      43 = sildenafil. Compound 17b was inhibited by the FPR1 antagonist cyclosporin H 
      but not by soluble guanylate cyclase, nitric oxide synthase or cyclooxygenase 
      inhibitors. Under inflammatory conditions, the efficacy and potency of compound 
      17b were maintained, while iloprost and sildenafil were less effective. 
      Additionally, compound 17b inhibited secretion of PAH-relevant cytokines via 
      FPR2. CONCLUSIONS AND IMPLICATIONS: Vasodilation to compound 17b but not 
      standard-of-care vasodilators, is maintained under inflammatory conditions, with 
      additional inhibition of PAH-relevant cytokine release. This provides the first 
      evidence that targeting FPR, with biased agonist, simultaneously targets vascular 
      function and inflammation, supporting the development of FPR-based 
      pharmacotherapy to treat PAH.
CI  - (c) 2023 The Authors. British Journal of Pharmacology published by John Wiley & 
      Sons Ltd on behalf of British Pharmacological Society.
FAU - Studley, William R
AU  - Studley WR
AUID- ORCID: 0000-0001-5020-6013
AD  - Department of Pharmacology, Biomedicine Discovery Institute, Monash University, 
      Clayton, Victoria, Australia.
FAU - Lamanna, Emma
AU  - Lamanna E
AD  - Department of Pharmacology, Biomedicine Discovery Institute, Monash University, 
      Clayton, Victoria, Australia.
FAU - Martin, Katherine A
AU  - Martin KA
AD  - Department of Pharmacology, Biomedicine Discovery Institute, Monash University, 
      Clayton, Victoria, Australia.
FAU - Nold-Petry, Claudia A
AU  - Nold-Petry CA
AUID- ORCID: 0000-0002-7439-3834
AD  - Department of Paediatrics, Monash University, Clayton, Victoria, Australia.
AD  - Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, 
      Australia.
FAU - Royce, Simon G
AU  - Royce SG
AUID- ORCID: 0000-0001-5841-1775
AD  - Department of Pharmacology, Biomedicine Discovery Institute, Monash University, 
      Clayton, Victoria, Australia.
FAU - Woodman, Owen L
AU  - Woodman OL
AUID- ORCID: 0000-0003-3759-1396
AD  - Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 
      Victoria, Australia.
FAU - Ritchie, Rebecca H
AU  - Ritchie RH
AUID- ORCID: 0000-0002-8610-0058
AD  - Department of Pharmacology, Biomedicine Discovery Institute, Monash University, 
      Clayton, Victoria, Australia.
AD  - Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 
      Victoria, Australia.
AD  - Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
FAU - Qin, Cheng Xue
AU  - Qin CX
AUID- ORCID: 0000-0003-2169-2686
AD  - Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 
      Victoria, Australia.
AD  - Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
FAU - Bourke, Jane E
AU  - Bourke JE
AUID- ORCID: 0000-0001-7314-9234
AD  - Department of Pharmacology, Biomedicine Discovery Institute, Monash University, 
      Clayton, Victoria, Australia.
LA  - eng
GR  - ID1187989/National Health and Medical Research Council/
GR  - Victorian Government of Australia's Operational Infrastructure Support Program/
GR  - National Heart Foundation of Australia Future Leader Fellowship/
GR  - Australian Government Research Training Program (RTP) Scholarship/
PT  - Journal Article
DEP - 20230901
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
SB  - IM
OTO - NOTNLM
OT  - formyl peptide receptor
OT  - inflammation
OT  - precision-cut lung slice
OT  - pulmonary arterial hypertension
OT  - respiratory pharmacology
OT  - vasodilation
EDAT- 2023/09/02 10:43
MHDA- 2023/09/02 10:43
CRDT- 2023/09/02 00:43
PHST- 2023/07/03 00:00 [revised]
PHST- 2022/09/23 00:00 [received]
PHST- 2023/07/05 00:00 [accepted]
PHST- 2023/09/02 10:43 [pubmed]
PHST- 2023/09/02 10:43 [medline]
PHST- 2023/09/02 00:43 [entrez]
AID - 10.1111/bph.16231 [doi]
PST - aheadofprint
SO  - Br J Pharmacol. 2023 Sep 1. doi: 10.1111/bph.16231.