PMID- 34767813
OWN - NLM
STAT- MEDLINE
DCOM- 20220302
LR  - 20230401
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Print)
IS  - 0002-9440 (Linking)
VI  - 192
IP  - 2
DP  - 2022 Feb
TI  - Dedicator of Cytokinesis 2 (DOCK2) Deficiency Attenuates Lung Injury Associated 
      with Chronic High-Fat and High-Fructose Diet-Induced Obesity.
PG  - 226-238
LID - S0002-9440(21)00474-0 [pii]
LID - 10.1016/j.ajpath.2021.10.011 [doi]
AB  - Obesity is a major risk factor for lung disease development. However, little is 
      known about the impact of chronic high-fat and high-fructose (HFHF) diet-induced 
      obesity on lung inflammation and subsequent pulmonary fibrosis. Herein we 
      hypothesized that dedicator of cytokinesis 2 (DOCK2) promotes a proinflammatory 
      phenotype of lung fibroblasts (LFs) to elicit lung injury and fibrosis in chronic 
      HFHF diet-induced obesity. An HFHF diet for 20 weeks induced lung inflammation 
      and profibrotic changes in wild-type C57BL/6 mice. CD68 and monocyte 
      chemoattractant protein-1 (MCP-1) expression were notably increased in the lungs 
      of wild-type mice fed an HFHF diet. An HFHF diet further increased lung DOCK2 
      expression that co-localized with fibroblast-specific protein 1, suggesting a 
      role of DOCK2 in regulating proinflammatory phenotype of LFs. Importantly, DOCK2 
      knockout protected mice from lung inflammation and fibrosis induced by a HFHF 
      diet. In primary human LFs, tumor necrosis factor-alpha (TNF-alpha) and IL-1beta induced 
      DOCK2 expression concurrent with MCP-1, IL-6, and matrix metallopeptidase 2. 
      DOCK2 knockdown suppressed TNF-alpha-induced expression of these molecules and 
      activation of phosphatidylinositol 3-kinase/AKT and NF-kappaB signaling pathways, 
      suggesting a mechanism of DOCK2-mediated proinflammatory and profibrotic changes 
      in human LFs. Taken together, these findings reveal a previously unrecognized 
      role of DOCK2 in regulating proinflammatory phenotype of LFs, potentiation of 
      lung inflammation, and pulmonary fibrosis in chronic HFHF diet-caused obesity.
CI  - Copyright (c) 2022 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Qian, Guoqing
AU  - Qian G
AD  - Department of Cellular and Molecular Biology, The University of Texas Health 
      Science Center at Tyler, Tyler, Texas.
FAU - Adeyanju, Oluwaseun
AU  - Adeyanju O
AD  - Department of Cellular and Molecular Biology, The University of Texas Health 
      Science Center at Tyler, Tyler, Texas.
FAU - Sunil, Christudas
AU  - Sunil C
AD  - Department of Cellular and Molecular Biology, The University of Texas Health 
      Science Center at Tyler, Tyler, Texas.
FAU - Huang, Steven K
AU  - Huang SK
AD  - Division of Pulmonary and Critical Care Medicine, University of Michigan Medical 
      School, Ann Arbor, Michigan.
FAU - Chen, Shi-You
AU  - Chen SY
AD  - Department of Physiology and Pharmacology, University of Georgia, Athens, 
      Georgia; Department of Surgery, School of Medicine, The University of Missouri, 
      Columbia, Missouri.
FAU - Tucker, Torry A
AU  - Tucker TA
AD  - Department of Cellular and Molecular Biology, The University of Texas Health 
      Science Center at Tyler, Tyler, Texas.
FAU - Idell, Steven
AU  - Idell S
AD  - Department of Cellular and Molecular Biology, The University of Texas Health 
      Science Center at Tyler, Tyler, Texas.
FAU - Guo, Xia
AU  - Guo X
AD  - Department of Cellular and Molecular Biology, The University of Texas Health 
      Science Center at Tyler, Tyler, Texas; Department of Physiology and Pharmacology, 
      University of Georgia, Athens, Georgia. Electronic address: xia.guo@uthct.edu.
LA  - eng
GR  - R01 HL127203/HL/NHLBI NIH HHS/United States
GR  - R01 HL130133/HL/NHLBI NIH HHS/United States
GR  - R01 HL142853/HL/NHLBI NIH HHS/United States
GR  - K99 HL141583/HL/NHLBI NIH HHS/United States
GR  - R00 HL141583/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20211110
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Antigens, CD)
RN  - 0 (Antigens, Differentiation, Myelomonocytic)
RN  - 0 (CD68 protein, mouse)
RN  - 0 (Cytokines)
RN  - 0 (DOCK2 protein, mouse)
RN  - 0 (GTPase-Activating Proteins)
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 30237-26-4 (Fructose)
SB  - IM
MH  - Animals
MH  - Antigens, CD/genetics/metabolism
MH  - Antigens, Differentiation, Myelomonocytic/genetics/metabolism
MH  - Chronic Disease
MH  - Cytokines/genetics/metabolism
MH  - Diet, High-Fat/*adverse effects
MH  - Fibroblasts/metabolism/pathology
MH  - Fructose/*adverse effects/pharmacology
MH  - GTPase-Activating Proteins/*deficiency/metabolism
MH  - Guanine Nucleotide Exchange Factors/*deficiency/metabolism
MH  - Lung/*metabolism/pathology
MH  - Lung Injury/chemically induced/genetics/*metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Obesity/chemically induced/genetics/*metabolism/pathology
MH  - Signal Transduction
PMC - PMC8883439
EDAT- 2021/11/13 06:00
MHDA- 2022/03/03 06:00
PMCR- 2023/02/01
CRDT- 2021/11/12 20:13
PHST- 2021/04/19 00:00 [received]
PHST- 2021/09/21 00:00 [revised]
PHST- 2021/10/19 00:00 [accepted]
PHST- 2021/11/13 06:00 [pubmed]
PHST- 2022/03/03 06:00 [medline]
PHST- 2021/11/12 20:13 [entrez]
PHST- 2023/02/01 00:00 [pmc-release]
AID - S0002-9440(21)00474-0 [pii]
AID - 10.1016/j.ajpath.2021.10.011 [doi]
PST - ppublish
SO  - Am J Pathol. 2022 Feb;192(2):226-238. doi: 10.1016/j.ajpath.2021.10.011. Epub 
      2021 Nov 10.