Smooth muscle brain‐derived neurotrophic factor contributes to airway hyperreactivity in a mouse model of allergic asthma

Britt, Rodney D.; Thompson, Michael A.; Wicher, S.A.; Manlove, L.; Roesler, A.M.; Fang, Yun; Roos, Carolyn M; Smith, Leslie; Miller, Jordan D.; Pabelick, Christina M.; Prakash, Y. S.

doi:10.1096/fj.201801002r

Cited by 30 publications

(37 citation statements)

References 59 publications

(84 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we employed MA induced model of asthma, as it is considered to be robust and the most effective model of mimicking human asthma in murine models (Aravamudan et al, 2012;Iijima et al, 2014;Yarova et al, 2015;Ambhore et al, 2019a;Britt et al, 2019). Airway mechanics were determined using the forced oscillation technique (FOT) of the FlexiVent Fx1 module, which is an invasive endpoint technique that delivers parameters like airway resistance (Rrs), compliance (Crs), elastance (Ers), tissue elasticity (H) and tissue damping (G), which together depict the overall lung function (Aravamudan et al, 2012;Ambhore et al, 2019a).…”

Section: Discussionmentioning

confidence: 99%

“…Fibronectin, like collagen is another ECM protein marker that indicates the extent of airway remodeling (Shoji et al, 1990;Shiels et al, 1999). Vimentin is considered as a marker for detecting fibrosis, which indicates phenotype changes in ASM to fibroblast (Wang et al, 2006;Wang et al, 2007;Slats et al, 2008;Tang and Gerlach, 2017); whereas, a-SMA is a smooth muscle specific marker, ASM in this case (Ambhore et al, 2019a;Britt et al, 2019;Loganathan et al, 2019). Immunofluorescence studies of mice lung sections indicate increased expression of fibronectin, vimentin and a-SMA in mice from all three-study populations exposed to MA, especially in ERb KO mice, indicating significant remodeling of the airways in the absence of ERb implicating a crucial role for ERb in regulating airway remodeling.…”

Section: Discussionmentioning

confidence: 99%

“…Mice allotted to mixed allergen (MA) group were administered intranasally with a mixture of equal amounts (10 mg) of ovalbumin (Sigma Aldrich, USA), and extracts from Alternaria alternata, Aspergillus fumigatus, and Dermatophagoides farinae (Greer labs, USA) for 4 weeks in phosphate-buffered saline (PBS), while PBS alone was administered as a vehicle for 28 days on every alternate day ( Figure 1A) (Iijima et al, 2014;Yarova et al, 2015;Ambhore et al, 2019a;Britt et al, 2019;Loganathan et al, 2019).…”

Section: Mixed Allergen (Ma) Exposurementioning

confidence: 99%

“…Standard techniques were employed for histopathological studies using H&E for morphological analysis (Aravamudan et al, 2012;Raju et al, 2014;Liu et al, 2017;Ambhore et al, 2019a;Britt et al, 2019). For SRFG staining to detect collagen deposition standard technique was followed as per manufacturer's instructions (Chrondex, Inc., USA).…”

Section: Histopathology Using Hematoxylin and Eosin (Hande) And Sirius mentioning

confidence: 99%

See 3 more Smart Citations

Role of Estrogen Receptors α and β in a Murine Model of Asthma: Exacerbated Airway Hyperresponsiveness and Remodeling in ERβ Knockout Mice

et al. 2020

View full text Add to dashboard Cite

Epidemiological data suggests increased prevalence of asthma in females than males, suggesting a plausible role for sex-steroids, especially estrogen in the lungs. Estrogen primarily acts through estrogen-receptors (ERa and ERb), which play a differential role in asthma. Our previous studies demonstrated increased expression of ERb in asthmatic human airway smooth muscle (ASM) cells and its activation diminished ASM proliferation in vitro and airway hyperresponsiveness (AHR) in vivo in a mouse (wild-type, WT) model of asthma. In this study, we evaluated the receptor specific effect of circulating endogenous estrogen in regulating AHR and remodeling using ERa and ERb knockout (KO) mice. C57BL/6J WT, ERa KO, and ERb KO mice were challenged intranasally with a mixedallergen (MA) or PBS. Lung function was measured using flexiVent followed by collection of broncho-alveolar lavage fluid for differential leukocyte count (DLC), histology using hematoxylin and eosin (H&E) and Sirius red-fast green (SRFG) and detecting asmooth muscle actin (a-SMA), fibronectin and vimentin expression using immunofluorescence (IF). Resistance (Rrs), elastance (Ers), tissue-damping (G) and tissue-elasticity (H) were significantly increased, whereas compliance (Crs) was significantly decreased in WT, ERa KO, and ERb KO mice (males and females) challenged with MA compared to PBS. Interestingly, ERb KO mice showed declined lung function compared to ERa KO and WT mice at baseline. MA induced AHR, remodeling and immune-cell infiltration was more prominent in females compared to males across all populations, while ERb KO females showed maximum AHR and DLC, except for neutrophil count. Histology using H&E suggests increased smooth muscle mass in airways with recruitment of inflammatory cells, while SRFG staining showed increased collagen deposition in MA challenged ERb KO mice compared to ERa KO and WT mice (males and females), with pronounced effects in ERb KO females. Furthermore, IF studies showed increased expression of a-SMA, fibronectin and vimentin in MA challenged populations compared to PBS, with prominent changes in ERb KO females. This novel study indicates ERb plays a pivotal role

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mixed Allergen (Ma) Exposurementioning

confidence: 99%

Section: Histopathology Using Hematoxylin and Eosin (Hande) And Sirius mentioning

confidence: 99%

See 2 more Smart Citations

Role of Estrogen Receptors α and β in a Murine Model of Asthma: Exacerbated Airway Hyperresponsiveness and Remodeling in ERβ Knockout Mice

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The TrkB receptor is expressed in airway nerve endings 18 and is crucial for the regulation of airway innervation induced by perinatal inflammation 19 . Moreover, BDNF/TrkB signaling contributes to AHR in animal models of asthma 21,22 …”

Section: Introductionmentioning

confidence: 99%

Cholinergic neuroplasticity in asthma driven by TrkB signaling

et al. 2020

Self Cite

View full text Add to dashboard Cite

Parasympathetic neurons in the airways control bronchomotor tone. Increased activity of cholinergic neurons are mediators of airway hyperresponsiveness (AHR) in asthma, however, mechanisms are not elucidated. We describe remodeling of the cholinergic neuronal network in asthmatic airways driven by brain‐derived neurotrophic factor (BDNF) and Tropomyosin receptor kinase B (TrkB). Human bronchial biopsies were stained for cholinergic marker vesicular acetylcholine transporter (VAChT). Human lung gene expression and single nucleotide polymorphisms (SNP) in neuroplasticity‐related genes were compared between asthma and healthy patients. Wild‐type (WT) and mutated TrkB knock‐in mice (Ntrk2tm1Ddg/J) with impaired BDNF signaling were chronically exposed to ovalbumin (OVA). Neuronal VAChT staining and airway narrowing in response to electrical field stimulation in precision cut lung slices (PCLS) were assessed. Increased cholinergic fibers in asthmatic airway biopsies was found, paralleled by increased TrkB gene expression in human lung tissue, and SNPs in the NTRK2 [TrkB] and BDNF genes linked to asthma. Chronic allergen exposure in mice resulted in increased density of cholinergic nerves, which was prevented by inhibiting TrkB. Increased nerve density resulted in AHR in vivo and in increased nerve‐dependent airway reactivity in lung slices mediated via TrkB. These findings show cholinergic neuroplasticity in asthma driven by TrkB signaling and suggest that the BDNF‐TrkB pathway may be a potential target.

show abstract

Glial‐derived neurotrophic factor in human airway smooth muscle

Bhallamudi

Roos

Teske

et al. 2021

Journal Cellular Physiology

Self Cite

View full text Add to dashboard Cite

Airway smooth muscle (ASM) cells modulate the local airway milieu via production of inflammatory mediators and growth factors including classical neurotrophins, such as brain-derived neurotrophic factor (BDNF). The glial cell-derived neurotrophic factor (GDNF) family of ligands (GFLs) are nonclassical neurotrophins and their role in the airway is barely understood. The major GFLs, GDNF and Neurturin (NRTN) bind to GDNF family receptor (GFR) α1 and α2 respectively that pair with Ret receptor to accomplish signaling. In this study, we found GDNF is expressed in human lung and increased in adult asthma, while human ASM expresses GDNF and its receptors. Accordingly, we used human ASM cells to test the hypothesis that ASM expression and autocrine signaling by GFLs regulate [Ca 2+ ] i . Serum-deprived ASM cells from nonasthmatics were exposed to 10 ng/ml GDNF or NRTN for 15 min (acute) or 24 h (chronic). In fura-2 loaded cells, acute GDNF or NRTN alone induced [Ca 2+ ] i responses, and further enhanced responses to 1 µM ACh or 10 µM histamine. Ret inhibitor (SPP86; 10 µM) or specific GDNF chelator GFRα1-Fc (1 µg/ml) showed roles of these receptors in GDNF effects. In contrast, NRTN did not enhance [Ca 2+ ] i response to histamine. Furthermore, conditioned media of nonasthmatic and asthmatic ASM cells showed GDNF secretion. SPP86, Ret inhibitor and GFRα1-Fc chelator markedly decreased [Ca 2+ ] i response compared with vehicle, highlighting autocrine effects of secreted GDNF. Chronic GDNF treatment increased histamine-induced myosin light chain phosphorylation. These novel data demonstrate GFLs particularly GDNF/GFRα1 influence ASM [Ca 2+ ] i and raise the possibility that GFLs are potential targets of airway hyperresponsiveness.

show abstract

Smooth muscle brain‐derived neurotrophic factor contributes to airway hyperreactivity in a mouse model of allergic asthma

Cited by 30 publications

References 59 publications

Role of Estrogen Receptors α and β in a Murine Model of Asthma: Exacerbated Airway Hyperresponsiveness and Remodeling in ERβ Knockout Mice

Role of Estrogen Receptors α and β in a Murine Model of Asthma: Exacerbated Airway Hyperresponsiveness and Remodeling in ERβ Knockout Mice

Cholinergic neuroplasticity in asthma driven by TrkB signaling

Glial‐derived neurotrophic factor in human airway smooth muscle

Contact Info

Product

Resources

About