Inner ear dysfunction in caspase-3 deficient mice

Background Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. Methods Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. Results Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. Conclusion Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

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TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00102.2012 ◽

2012 ◽

Vol 303 (9) ◽

pp. L748-L757 ◽

Cited By ~ 40

Author(s):

Chang Hyeok An ◽

Xiao Mei Wang ◽

Hilaire C. Lam ◽

Emeka Ifedigbo ◽

George R. Washko ◽

...

Keyword(s):

Epithelial Cells ◽

Lung Disease ◽

Pulmonary Emphysema ◽

Obstructive Lung Disease ◽

Caspase 3 ◽

Chronic Obstructive Lung Disease ◽

Chronic Obstructive ◽

Tlr4 Expression ◽

Wild Type ◽

Deficient Mice

Toll-like receptors (TLRs) exert important nonimmune functions in lung homeostasis. TLR4 deficiency promotes pulmonary emphysema. We examined the role of TLR4 in regulating cigarette smoke (CS)-induced autophagy, apoptosis, and emphysema. Lung tissue was obtained from chronic obstructive lung disease (COPD) patients. C3H/HeJ ( Tlr4-mutated) mice and C57BL/10ScNJ ( Tlr4-deficient) mice and their respective control strains were exposed to chronic CS or air. Human or mouse epithelial cells (wild-type, Tlr4-knockdown, and Tlr4-deficient) were exposed to CS-extract (CSE). Samples were analyzed for TLR4 expression, and for autophagic or apoptotic proteins by Western blot analysis or confocal imaging. Chronic obstructive lung disease lung tissues and human pulmonary epithelial cells exposed to CSE displayed increased TLR4 expression, and increased autophagic [microtubule-associated protein-1 light-chain-3B (LC3B)] and apoptotic (cleaved caspase-3) markers. Beas-2B cells transfected with TLR4 siRNA displayed increased expression of LC3B relative to control cells, basally and after exposure to CSE. The basal and CSE-inducible expression of LC3B and cleaved caspase-3 were elevated in pulmonary alveolar type II cells from Tlr4-deficient mice. Wild-type mice subjected to chronic CS-exposure displayed airspace enlargement;, however, the Tlr4-mutated or Tlr4-deficient mice exhibited a marked increase in airspace relative to wild-type mice after CS-exposure. The Tlr4-mutated or Tlr4-deficient mice showed higher levels of LC3B under basal conditions and after CS exposure. The expression of cleaved caspase-3 was markedly increased in Tlr4-deficient mice exposed to CS. We describe a protective regulatory function of TLR4 against emphysematous changes of the lung in response to CS.

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Characterization of Social Behaviors in caspase-3 deficient mice

Scientific Reports ◽

10.1038/srep18335 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 17

Author(s):

Shih-Ching Lo ◽

Kimberly Scearce-Levie ◽

Morgan Sheng

Keyword(s):

Caspase 3 ◽

Social Behaviors ◽

Deficient Mice

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Tinnitus and Other Auditory Problems – Occupational Noise Exposure below Risk Limits May Cause Inner Ear Dysfunction

PLoS ONE ◽

10.1371/journal.pone.0097377 ◽

2014 ◽

Vol 9 (5) ◽

pp. e97377 ◽

Cited By ~ 8

Author(s):

Ann-Cathrine Lindblad ◽

Ulf Rosenhall ◽

Åke Olofsson ◽

Björn Hagerman

Keyword(s):

Inner Ear ◽

Noise Exposure ◽

Occupational Noise ◽

Occupational Noise Exposure ◽

Risk Limits ◽

Inner Ear Dysfunction

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Inner ear is a target for insulin signaling and insulin resistance: evidence from mice and auditory HEI-OC1 cells

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000820 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000820 ◽

Cited By ~ 1

Author(s):

Ann-Ki Pålbrink ◽

Franziska Kopietz ◽

Björn Morén ◽

René In 't Zandt ◽

Federico Kalinec ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Kinase ◽

Inner Ear ◽

Insulin Signaling ◽

Organ Of Corti ◽

Target Tissue ◽

Dependent Manner ◽

The Impact ◽

Rate Limiting ◽

Inner Ear Dysfunction

ObjectiveThe mechanisms underlying the association between diabetes and inner ear dysfunction are not known yet. The aim of the present study is to evaluate the impact of obesity/insulin resistance on inner ear fluid homeostasis in vivo, and to investigate whether the organ of Corti could be a target tissue for insulin signaling using auditory House Ear Institute-Organ of Corti 1 (HEI-OC1) cells as an in vitro model.MethodsHigh fat diet (HFD) fed C57BL/6J mice were used as a model to study the impact of insulin resistance on the inner ear. In one study, 12 C57BL/6J mice were fed either control diet or HFD and the size of the inner ear endolymphatic fluid compartment (EFC) was measured after 30 days using MRI and gadolinium contrast as a read-out. In another study, the size of the inner ear EFC was evaluated in eight C57BL/6J mice both before and after HFD feeding, with the same techniques. HEI-OC1 auditory cells were used as a model to investigate insulin signaling in organ of Corti cells.ResultsHFD feeding induced an expansion of the EFC in C57BL/6J mice, a hallmark of inner ear dysfunction. Insulin also induced phosphorylation of protein kinase B (PKB/Akt) at Ser473, in a PI3-kinase-dependent manner. The phosphorylation of PKB was inhibited by isoproterenol and IBMX, a general phosphodiesterase (PDE) inhibitor. PDE1B, PDE4D and the insulin-sensitive PDE3B were found expressed and catalytically active in HEI-OC1 cells. Insulin decreased and AICAR, an activator of AMP-activated protein kinase, increased the phosphorylation at the inhibitory Ser79 of acetyl-CoA carboxylase, the rate-limiting enzyme in de novo lipogenesis. Furthermore, the activity of hormone-sensitive lipase, the rate-limiting enzyme in lipolysis, was detected in HEI-OC1 cells.ConclusionsThe organ of Corti could be a target tissue for insulin action, and inner ear insulin resistance might contribute to the association between diabetes and inner ear dysfunction.

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