Caveolin-1 scaffolding domain peptide prevents hyperoxia-induced airway remodeling in a neonatal mouse model

Reactive airway diseases are significant sources of pulmonary morbidity in neonatal and pediatric patients. Supplemental oxygen exposure in premature infants contributes to airway diseases such as asthma and promotes development of airway remodeling, characterized by increased airway smooth muscle (ASM) mass and extracellular matrix (ECM) deposition. Decreased plasma membrane caveolin-1 (CAV1) expression has been implicated in airway disease and may contribute to airway remodeling and hyperreactivity. Here, we investigated the impact of clinically relevant moderate hyperoxia (50% O2) on airway remodeling and caveolar protein expression in a neonatal mouse model. Within 12 h of birth, litters of B6129SF2J mice were randomized to room air (RA) or 50% hyperoxia exposure for 7 days with or without caveolin-1 scaffolding domain peptide (CSD; caveolin-1 mimic; 10 µl, 0.25 mM daily via intraperitoneal injection) followed by 14 days of recovery in normoxia. Moderate hyperoxia significantly increased airway reactivity and decreased pulmonary compliance at 3 wk. Histologic assessment demonstrated airway wall thickening and increased ASM mass following hyperoxia. RNA from isolated ASM demonstrated significant decreases in CAV1 and cavin-1 in hyperoxia-exposed animals while cavin-3 was increased. Supplementation with intraperitoneal CSD mitigated both the physiologic and histologic changes observed with hyperoxia. Overall, these data show that moderate hyperoxia is detrimental to developing airway and may predispose to airway reactivity and remodeling. Loss of CAV1 is one mechanism through which hyperoxia produces these deleterious effects. Supplementation of CAV1 using CSD or similar analogs may represent a new therapeutic avenue for blunting hyperoxia-induced pulmonary damage in neonates.

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Increased airway reactivity in a neonatal mouse model of continuous positive airway pressure

Pediatric Research ◽

10.1038/pr.2015.90 ◽

2015 ◽

Vol 78 (2) ◽

pp. 145-151 ◽

Cited By ~ 9

Author(s):

Catherine A. Mayer ◽

Richard J. Martin ◽

Peter M. MacFarlane

Keyword(s):

Continuous Positive Airway Pressure ◽

Mouse Model ◽

Airway Pressure ◽

Positive Airway Pressure ◽

Neonatal Mouse ◽

Airway Reactivity

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Effects of antenatal lipopolysaccharide and postnatal hyperoxia on airway reactivity and remodeling in a neonatal mouse model

Pediatric Research ◽

10.1038/pr.2015.232 ◽

2015 ◽

Vol 79 (3) ◽

pp. 391-400 ◽

Cited By ~ 12

Author(s):

Arij Faksh ◽

Rodney D. Britt ◽

Elizabeth R. Vogel ◽

Ine Kuipers ◽

Michael A. Thompson ◽

...

Keyword(s):

Mouse Model ◽

Neonatal Mouse ◽

Airway Reactivity

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Prenatal Maternal Lipopolysaccharide and Mild Newborn Hyperoxia Increase Intrapulmonary Airway but Not Vessel Reactivity in a Mouse Model

Children ◽

10.3390/children8030195 ◽

2021 ◽

Vol 8 (3) ◽

pp. 195

Author(s):

Margaret E. Kuper-Sassé ◽

Peter M. MacFarlane ◽

Catherine A. Mayer ◽

Richard J. Martin ◽

Y. S. Prakash ◽

...

Keyword(s):

Mouse Model ◽

Respiratory Distress ◽

Preterm Delivery ◽

Vascular Reactivity ◽

Supplemental Oxygen ◽

Maternal Infection ◽

Airway Reactivity ◽

Hyperoxia Exposure ◽

Neonatal Respiratory Distress ◽

Preterm Newborns

Maternal infection is a risk for preterm delivery. Preterm newborns often require supplemental oxygen to treat neonatal respiratory distress. Newborn hyperoxia exposure is associated with airway and vascular hyperreactivity, while the complications of maternal infection are variable. In a mouse model of prenatal maternal intraperitoneal lipopolysaccharide (LPS, embryonic day 18) with subsequent newborn hyperoxia (40% oxygen × 7 days) precision-cut living lung slices were used to measure intrapulmonary airway and vascular reactivity at 21 days of age. Hyperoxia increased airway reactivity to methacholine compared to room air controls. Prenatal maternal LPS did not alter airway reactivity in room air. Combined maternal LPS and hyperoxia exposures increased airway reactivity vs. controls, although maximal responses were diminished compared to hyperoxia alone. Vessel reactivity to serotonin did not significantly differ in hyperoxia or room air; however, prenatal maternal LPS appeared to attenuate vessel reactivity in room air. Following room air recovery, LPS with hyperoxia lungs displayed upregulated inflammatory and fibrosis genes compared to room air saline controls (TNFαR1, iNOS, and TGFβ). In this model, mild newborn hyperoxia increases airway but not vessel reactivity. Prenatal maternal LPS did not further increase hyperoxic airway reactivity. However, inflammatory genes remain upregulated weeks after recovery from maternal LPS and newborn hyperoxia exposures.

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1875-P: The Impact of Carbohydrate/Fat Intake Balance on Beta-Cell Dedifferentiation and Fatty Liver in Obese Mouse Model

Diabetes ◽

10.2337/db20-1875-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 1875-P ◽

Cited By ~ 2

Author(s):

EMI ISHIDA ◽

XIAO LEI ◽

EIJIRO YAMADA ◽

SHUICHI OKADA ◽

MASANOBU YAMADA

Keyword(s):

Mouse Model ◽

Beta Cell ◽

Fatty Liver ◽

Obese Mouse ◽

Fat Intake ◽

Cell Dedifferentiation ◽

The Impact

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Structural and functional brain-wide alterations in A350V Iqsec2 mutant mice displaying autistic-like behavior

Translational Psychiatry ◽

10.1038/s41398-021-01289-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daniela Lichtman ◽

Eyal Bergmann ◽

Alexandra Kavushansky ◽

Nadav Cohen ◽

Nina S. Levy ◽

...

Keyword(s):

Social Behavior ◽

Functional Connectivity ◽

Mouse Model ◽

Ampa Receptor ◽

Social Preference ◽

Autism Spectrum ◽

Receptor Trafficking ◽

Anterior Cingulate ◽

The Impact ◽

Ampa Receptor Trafficking

AbstractIQSEC2 is an X-linked gene that is associated with autism spectrum disorder (ASD), intellectual disability, and epilepsy. IQSEC2 is a postsynaptic density protein, localized on excitatory synapses as part of the NMDA receptor complex and is suggested to play a role in AMPA receptor trafficking and mediation of long-term depression. Here, we present brain-wide structural volumetric and functional connectivity characterization in a novel mouse model with a missense mutation in the IQ domain of IQSEC2 (A350V). Using high-resolution structural and functional MRI, we show that animals with the A350V mutation display increased whole-brain volume which was further found to be specific to the cerebral cortex and hippocampus. Moreover, using a data-driven approach we identify putative alterations in structure–function relations of the frontal, auditory, and visual networks in A350V mice. Examination of these alterations revealed an increase in functional connectivity between the anterior cingulate cortex and the dorsomedial striatum. We also show that corticostriatal functional connectivity is correlated with individual variability in social behavior only in A350V mice, as assessed using the three-chamber social preference test. Our results at the systems-level bridge the impact of previously reported changes in AMPA receptor trafficking to network-level disruption and impaired social behavior. Further, the A350V mouse model recapitulates similarly reported brain-wide changes in other ASD mouse models, with substantially different cellular-level pathologies that nonetheless result in similar brain-wide alterations, suggesting that novel therapeutic approaches in ASD that result in systems-level rescue will be relevant to IQSEC2 mutations.

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Synapsin-caveolin-1 gene therapy preserves neuronal and synaptic morphology and prevents neurodegeneration in a mouse model of Alzheimer’s disease

Molecular Therapy — Methods & Clinical Development ◽

10.1016/j.omtm.2021.03.021 ◽

2021 ◽

Author(s):

Shanshan Wang ◽

Joseph S. Leem ◽

Sonia Podvin ◽

Vivian Hook ◽

Natalia Kleschevnikov ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gene Therapy ◽

Mouse Model ◽

Caveolin 1 ◽

Model Of Alzheimer’S Disease

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Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01796-4 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Paulo L. Pfitzinger ◽

Laura Fangmann ◽

Kun Wang ◽

Elke Demir ◽

Engin Gürlevik ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Tumor Stage ◽

Ache Inhibitors ◽

Impact On Survival ◽

The Impact ◽

Ache Expression ◽

Cholinergic Activation

Abstract Background Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. Methods We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/−physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. Results We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. Conclusion For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.

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