PMID- 35150970
OWN - NLM
STAT- MEDLINE
DCOM- 20220310
LR  - 20220716
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 50
DP  - 2022 Apr
TI  - Fatty acid nitroalkene reversal of established lung fibrosis.
PG  - 102226
LID - S2213-2317(21)00386-4 [pii]
LID - 10.1016/j.redox.2021.102226 [doi]
LID - 102226
AB  - Tissue fibrosis occurs in response to dysregulated metabolism, pro-inflammatory 
      signaling and tissue repair reactions. For example, lungs exposed to 
      environmental toxins, cancer therapies, chronic inflammation and other stimuli 
      manifest a phenotypic shift to activated myofibroblasts and progressive and often 
      irreversible lung tissue scarring. There are no therapies that stop or reverse 
      fibrosis. The 2 FDA-approved anti-fibrotic drugs at best only slow the 
      progression of fibrosis in humans. The present study was designed to test whether 
      a small molecule electrophilic nitroalkene, nitro-oleic acid (NO(2)-OA), could 
      reverse established pulmonary fibrosis induced by the intratracheal 
      administration of bleomycin in C57BL/6 mice. After 14 d of bleomycin-induced 
      fibrosis development in vivo, lungs were removed, sectioned and precision-cut 
      lung slices (PCLS) from control and bleomycin-treated mice were cultured ex vivo 
      for 4 d with either vehicle or NO(2)-OA (5 muM). Biochemical and morphological 
      analyses showed that over a 4 d time frame, NO(2)-OA significantly inhibited 
      pro-inflammatory mediator and growth factor expression and reversed key indices 
      of fibrosis (hydroxyproline, collagen 1A1 and 3A1, fibronectin-1). Quantitative 
      image analysis of PCLS immunohistology reinforced these observations, revealing 
      that NO(2)-OA suppressed additional hallmarks of the fibrotic response, including 
      alveolar epithelial cell loss, myofibroblast differentiation and proliferation, 
      collagen and alpha-smooth muscle actin expression. NO(2)-OA also accelerated collagen 
      degradation by resident macrophages. These effects occurred in the absence of the 
      recognized NO(2)-OA modulation of circulating and migrating immune cell 
      activation. Thus, small molecule nitroalkenes may be useful agents for reversing 
      pathogenic fibrosis of lung and other organs.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Koudelka, Adolf
AU  - Koudelka A
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh, School 
      of Medicine, E1340 BST, 200 Lothrop Street, Pittsburgh, PA, 15261, USA. 
      Electronic address: koudelka@pitt.edu.
FAU - Cechova, Veronika
AU  - Cechova V
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh, School 
      of Medicine, E1340 BST, 200 Lothrop Street, Pittsburgh, PA, 15261, USA.
FAU - Rojas, Mauricio
AU  - Rojas M
AD  - Department of Medicine, University of Pittsburgh, School of Medicine, E1246 BST, 
      200 Lothrop Street, Pittsburgh, PA, 15213, USA; Department of Internal Medicine, 
      Ohio State University, 201 Davis Heart & Lung Research Institute, 473 W. 12th 
      Avenue Columbus, Ohio, 43210, USA.
FAU - Mitash, Nilay
AU  - Mitash N
AD  - Department of Medicine, University of Pittsburgh, School of Medicine, E1246 BST, 
      200 Lothrop Street, Pittsburgh, PA, 15213, USA.
FAU - Bondonese, Anna
AU  - Bondonese A
AD  - Department of Medicine, University of Pittsburgh, School of Medicine, E1246 BST, 
      200 Lothrop Street, Pittsburgh, PA, 15213, USA.
FAU - St Croix, Claudette
AU  - St Croix C
AD  - Department of Cell Biology, University of Pittsburgh, School of Medicine, S224 
      BST, 3500 Terrace Street, Pittsburgh, PA, 15261, USA.
FAU - Ross, Mark A
AU  - Ross MA
AD  - Department of Cell Biology, University of Pittsburgh, School of Medicine, S224 
      BST, 3500 Terrace Street, Pittsburgh, PA, 15261, USA.
FAU - Freeman, Bruce A
AU  - Freeman BA
AD  - Department of Pharmacology and Chemical Biology, University of Pittsburgh, School 
      of Medicine, E1340 BST, 200 Lothrop Street, Pittsburgh, PA, 15261, USA. 
      Electronic address: freerad@pitt.edu.
LA  - eng
GR  - P01 HL103455/HL/NHLBI NIH HHS/United States
GR  - R01 HL058115/HL/NHLBI NIH HHS/United States
GR  - R01 HL064937/HL/NHLBI NIH HHS/United States
GR  - U01 HL145550/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20211229
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 0 (Fatty Acids)
RN  - 11056-06-7 (Bleomycin)
SB  - IM
MH  - Animals
MH  - Bleomycin/adverse effects
MH  - *Fatty Acids/therapeutic use
MH  - Fibrosis
MH  - Lung/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Pulmonary Fibrosis/chemically induced/drug therapy/pathology
PMC - PMC8844680
OTO - NOTNLM
OT  - Electrophile
OT  - Fibrosis
OT  - Inflammation
OT  - Lung
OT  - Nitro-fatty acid
OT  - Nitroalkene
EDAT- 2022/02/13 06:00
MHDA- 2022/03/11 06:00
PMCR- 2021/12/29
CRDT- 2022/02/12 20:11
PHST- 2021/10/22 00:00 [received]
PHST- 2021/12/17 00:00 [revised]
PHST- 2021/12/27 00:00 [accepted]
PHST- 2022/02/13 06:00 [pubmed]
PHST- 2022/03/11 06:00 [medline]
PHST- 2022/02/12 20:11 [entrez]
PHST- 2021/12/29 00:00 [pmc-release]
AID - S2213-2317(21)00386-4 [pii]
AID - 102226 [pii]
AID - 10.1016/j.redox.2021.102226 [doi]
PST - ppublish
SO  - Redox Biol. 2022 Apr;50:102226. doi: 10.1016/j.redox.2021.102226. Epub 2021 Dec 
      29.