PMID- 35521223
OWN - NLM
STAT- MEDLINE
DCOM- 20220509
LR  - 20220716
IS  - 2235-2988 (Electronic)
IS  - 2235-2988 (Linking)
VI  - 12
DP  - 2022
TI  - Nrf2 Activation Protects Against Organic Dust and Hydrogen Sulfide Exposure 
      Induced Epithelial Barrier Loss and K. pneumoniae Invasion.
PG  - 848773
LID - 10.3389/fcimb.2022.848773 [doi]
LID - 848773
AB  - Agriculture workers report various respiratory symptoms owing to occupational 
      exposure to organic dust (OD) and various gases. Previously, we demonstrated that 
      pre-exposure to hydrogen sulfide (H(2)S) alters the host response to OD and 
      induces oxidative stress. Nrf2 is a master-regulator of host antioxidant response 
      and exposures to toxicants is known to reduce Nrf2 activity. The OD 
      exposure-induced lung inflammation is known to increase susceptibility to a 
      secondary microbial infection. We tested the hypothesis that repeated exposure to 
      OD or H(2)S leads to loss of Nrf2, loss of epithelial cell integrity and that 
      activation of Nrf2 rescues this epithelial barrier dysfunction. Primary normal 
      human bronchial epithelial (NHBE) cells or mouse precision cut-lung slices (PCLS) 
      were treated with media, swine confinement facility organic dust extract (ODE) or 
      H(2)S or ODE+H(2)S for one or five days. Cells were also pretreated with vehicle 
      control (DMSO) or RTA-408, a Nrf2 activator. Acute exposure to H(2)S and 
      ODE+H(2)S altered the cell morphology, decreased the viability as per the MTT 
      assay, and reduced the Nrf2 expression as well as increased the keap1 levels in 
      NHBE cells. Repeated exposure to ODE or H(2)S or ODE+H(2)S induced oxidative 
      stress and cytokine production, decreased tight junction protein occludin and 
      cytoskeletal protein ezrin expression, disrupted epithelial integrity and 
      resulted in increased Klebsiella pneumoniae invasion. RTA-408 (pharmacological 
      activator of Nrf2) activated Nrf2 by decreasing keap1 levels and reduced 
      ODE+H(2)S-induced changes including reversing loss of barrier integrity, 
      inflammatory cytokine production and microbial invasion in PCLS but not in NHBE 
      cell model. We conclude that Nrf2 activation has a partial protective function 
      against ODE and H(2)S.
CI  - Copyright (c) 2022 Shrestha, Massey, Bhat, Jelesijevic, Sahin, Zhang, Bailey, Poole 
      and Charavaryamath.
FAU - Shrestha, Denusha
AU  - Shrestha D
AD  - Department of Biomedical Sciences, Iowa State University, Ames, IA, United 
      States.
FAU - Massey, Nyzil
AU  - Massey N
AD  - Department of Biomedical Sciences, Iowa State University, Ames, IA, United 
      States.
FAU - Bhat, Sanjana Mahadev
AU  - Bhat SM
AD  - Department of Biomedical Sciences, Iowa State University, Ames, IA, United 
      States.
AD  - Immunobiology Interdepartmental Graduate Program, Iowa State University, Ames, 
      IA, United States.
FAU - Jelesijevic, Tomislav
AU  - Jelesijevic T
AD  - Department of Comparative Biomedical Sciences, Louisiana State University, Baton 
      Rouge, LA, United States.
FAU - Sahin, Orhan
AU  - Sahin O
AD  - Department of Veterinary Diagnostic and Production Animal Medicine, Iowa State 
      University, Ames, IA, United States.
FAU - Zhang, Qijing
AU  - Zhang Q
AD  - Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA, 
      United States.
FAU - Bailey, Kristina L
AU  - Bailey KL
AD  - Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep 
      Medicine, University of Nebraska Medical Center, Omaha, NE, United States.
FAU - Poole, Jill A
AU  - Poole JA
AD  - Department of Medicine, University of Nebraska Medical Center, Omaha, NE, United 
      States.
FAU - Charavaryamath, Chandrashekhar
AU  - Charavaryamath C
AD  - Department of Biomedical Sciences, Iowa State University, Ames, IA, United 
      States.
LA  - eng
GR  - U54 OH007548/OH/NIOSH CDC HHS/United States
GR  - R01 OH012045/OH/NIOSH CDC HHS/United States
GR  - U54 OH010162/OH/NIOSH CDC HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220419
PL  - Switzerland
TA  - Front Cell Infect Microbiol
JT  - Frontiers in cellular and infection microbiology
JID - 101585359
RN  - 0 (Cytokines)
RN  - 0 (Dust)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - YY9FVM7NSN (Hydrogen Sulfide)
SB  - IM
MH  - Animals
MH  - Cytokines/metabolism
MH  - Dust
MH  - *Hydrogen Sulfide/metabolism/pharmacology
MH  - Kelch-Like ECH-Associated Protein 1/metabolism
MH  - Klebsiella pneumoniae/metabolism
MH  - Mice
MH  - *NF-E2-Related Factor 2/metabolism
MH  - Oxidative Stress
MH  - Swine
PMC - PMC9062039
OTO - NOTNLM
OT  - H2S
OT  - K. pneumoniae
OT  - Nrf2
OT  - RTA-408
OT  - organic dust
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/05/07 06:00
MHDA- 2022/05/10 06:00
PMCR- 2022/01/01
CRDT- 2022/05/06 06:18
PHST- 2022/01/05 00:00 [received]
PHST- 2022/03/21 00:00 [accepted]
PHST- 2022/05/06 06:18 [entrez]
PHST- 2022/05/07 06:00 [pubmed]
PHST- 2022/05/10 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fcimb.2022.848773 [doi]
PST - epublish
SO  - Front Cell Infect Microbiol. 2022 Apr 19;12:848773. doi: 
      10.3389/fcimb.2022.848773. eCollection 2022.