PMID- 31511015
OWN - NLM
STAT- MEDLINE
DCOM- 20200303
LR  - 20200303
IS  - 1465-993X (Electronic)
IS  - 1465-9921 (Print)
IS  - 1465-9921 (Linking)
VI  - 20
IP  - 1
DP  - 2019 Sep 11
TI  - Interferon-gamma enhances the antifibrotic effects of pirfenidone by attenuating IPF 
      lung fibroblast activation and differentiation.
PG  - 206
LID - 10.1186/s12931-019-1171-2 [doi]
LID - 206
AB  - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) pathogenesis involves multiple 
      pathways, and combined antifibrotic therapy is needed for future IPF therapy. 
      Inhaled interferon-gamma (IFN-gamma) was recently shown to be safe and without systemic 
      effects in patients with IPF. AIM: To examine the in vitro effects of individual 
      and combined treatment with IFN-gamma and pirfenidone (PFD) on normal and IPF 
      fibroblast activation and extracellular matrix remodeling after TGF-beta1 and 
      PDGF-BB stimulation. METHODS: IPF and normal human lung fibroblasts (NHLF) were 
      treated with IFN-gamma, PFD or a combination of both drugs in the presence of either 
      TGF-beta1 or PDGF-BB. The effects of TGF-beta1 and PDGF-BB treatment on cell viability, 
      proliferation, differentiation and migration were examined. The expression of 
      collagen 1, matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs) 
      was analyzed using qPCR, Western blotting and gelatin zymography. Total collagen 
      content in conditioned media was also measured using a Sircol assay. RESULTS: 
      Compared to that of PFD, the effect of IFN-gamma in downregulating normal and IPF 
      lung fibroblast differentiation to myofibroblasts in response to TGF-beta1 was more 
      potent. Importantly, the combination of IFN-gamma and PFD had a possibly 
      synergistic/additive effect in inhibiting the TGF-beta1- and PDGF-BB-induced 
      proliferation, migration and differentiation of normal and IPF lung fibroblasts. 
      Furthermore, both drugs reversed TGF-beta1-induced effects on MMP-1, - 2, - 3, - 7, 
      and - 9, while only PFD promoted TIMP-1 and-2 expression and release. 
      CONCLUSIONS: Our findings demonstrate that the antifibrotic effects of IFN-gamma and 
      PFD on normal and IPF lung fibroblasts are different and complementary. 
      Combination therapy with inhaled IFN-gamma and PFD in IPF is promising and should be 
      further explored in IPF clinical trials.
FAU - Vu, Tuong N
AU  - Vu TN
AD  - Pulmonary, Critical Care and Sleep Division, Department of Medicine, Stony Brook 
      Medicine, Health Science Center, State University of New York at Stony Brook, HSC 
      T17 Room 040, Stony Brook, NY, 11794-8172, USA.
FAU - Chen, Xuesong
AU  - Chen X
AD  - Pulmonary, Critical Care and Sleep Division, Department of Medicine, Stony Brook 
      Medicine, Health Science Center, State University of New York at Stony Brook, HSC 
      T17 Room 040, Stony Brook, NY, 11794-8172, USA.
FAU - Foda, Hussein D
AU  - Foda HD
AD  - Pulmonary, Critical Care and Sleep Division, Department of Medicine, Stony Brook 
      Medicine, Health Science Center, State University of New York at Stony Brook, HSC 
      T17 Room 040, Stony Brook, NY, 11794-8172, USA.
AD  - Department of Medicine and Research, VAMC Northport, Stony Brook, NY, USA.
FAU - Smaldone, Gerald C
AU  - Smaldone GC
AD  - Pulmonary, Critical Care and Sleep Division, Department of Medicine, Stony Brook 
      Medicine, Health Science Center, State University of New York at Stony Brook, HSC 
      T17 Room 040, Stony Brook, NY, 11794-8172, USA.
FAU - Hasaneen, Nadia A
AU  - Hasaneen NA
AUID- ORCID: 0000-0001-6327-6029
AD  - Pulmonary, Critical Care and Sleep Division, Department of Medicine, Stony Brook 
      Medicine, Health Science Center, State University of New York at Stony Brook, HSC 
      T17 Room 040, Stony Brook, NY, 11794-8172, USA. 
      Nadia.Hasaneen@stonybrookmedicine.edu.
AD  - Department of Medicine and Research, VAMC Northport, Stony Brook, NY, USA. 
      Nadia.Hasaneen@stonybrookmedicine.edu.
LA  - eng
PT  - Journal Article
DEP - 20190911
PL  - England
TA  - Respir Res
JT  - Respiratory research
JID - 101090633
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Pyridones)
RN  - 82115-62-6 (Interferon-gamma)
RN  - D7NLD2JX7U (pirfenidone)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Anti-Inflammatory Agents, Non-Steroidal/*administration & dosage
MH  - Cell Differentiation/*drug effects/physiology
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Female
MH  - Fibroblasts/*drug effects/metabolism
MH  - Humans
MH  - Idiopathic Pulmonary Fibrosis/*drug therapy/metabolism/pathology
MH  - Interferon-gamma/*administration & dosage
MH  - Lung/drug effects/metabolism/pathology
MH  - Male
MH  - Pyridones/*administration & dosage
MH  - Young Adult
PMC - PMC6737625
OTO - NOTNLM
OT  - Fibroblast activation
OT  - IFN-gamma
OT  - IPF
OT  - MMPs
OT  - Pirfenidone
OT  - TIMPs
COIS- The authors declare that they have no competing interests. New York University 
      (NYU) and Stony Brook University (SBU) jointly hold patents on the treatment of 
      lung disease with inhaled interferon gamma. These patents are licensed to 
      InspiRx, Inc. Dr. Smaldone is a paid consultant to InspiRx, Inc.
EDAT- 2019/09/13 06:00
MHDA- 2020/03/04 06:00
PMCR- 2019/09/11
CRDT- 2019/09/13 06:00
PHST- 2018/09/10 00:00 [received]
PHST- 2019/08/23 00:00 [accepted]
PHST- 2019/09/13 06:00 [entrez]
PHST- 2019/09/13 06:00 [pubmed]
PHST- 2020/03/04 06:00 [medline]
PHST- 2019/09/11 00:00 [pmc-release]
AID - 10.1186/s12931-019-1171-2 [pii]
AID - 1171 [pii]
AID - 10.1186/s12931-019-1171-2 [doi]
PST - epublish
SO  - Respir Res. 2019 Sep 11;20(1):206. doi: 10.1186/s12931-019-1171-2.