Sensory receptors in the airways: neurochemical coding of smooth muscle-associated airway receptors and pulmonary neuroepithelial body innervation

Brouns, Inge; Proost, Ian De; Pintelon, Isabel; Timmermans, Jean‐Pierre; Adriaensen, Dirk

doi:10.1016/j.autneu.2006.02.006

Cited by 43 publications

(44 citation statements)

References 29 publications

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“…Moreover, reduction of TNF-α and TGF-β1 expression levels were observed, indicating that CGRP administration is likely to play a protective role in hyperoxiainduced ALI in neonatal rats through inhibition of oxidative stress and inflammatory response in various tissues. Reviews suggest that CGRP receptors are expressed on the cell surface of the bronchial epithelium, alveolar epithelial cells, and vascular endothelial cells (Brouns et al 2006). When CGRP binds to these receptors, the receptor-coupled G proteins will be activated, which leads to the induction of intracellular cyclic AMP formation (Bhandari et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Calcitonin Gene-Related Peptide Ameliorates Hyperoxia-Induced Lung Injury in Neonatal Rats

Dang

Yang

Wang

et al. 2012

Tohoku J. Exp. Med.

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Therapies with prolonged exposure to high-concentration oxygen are common in the treatment of critical pulmonary and cardiac conditions in newborns. However, prolonged exposure to hyperoxia could result in lung damages and developmental disorders manifested as acute lung injury and bronchopulmonary dysplasia, respectively. Calcitonin gene-related peptide (CGRP) has been shown to have a broad regulatory effect on the respiratory system. In this study, we explored the protective effects of CGRP on the hyperoxia-induced lung damage. Newborn Sprague-Dawley rats were randomly divided into three groups: normoxia, hyperoxia, and hyperoxia with CGRP. Hyperoxia groups were exposed to 95% oxygen for 14 days and treated once every other day with saline or CGRP. Hyperoxia exposure reduced the survival rate to 73%, when compared with the 93% survival rate observed in the normoxia group. The survival rate was improved to 84% with CGRP treatment. Treatment with CGRP under hyperoxia significantly alleviated the hyperoxia-induced lung histomorphological changes and the increases in leukocyte counts and total protein levels in bronchoalveolar lavage fluid that reflect the pulmonary microvasular damages. CGRP treatment also restored the decreased activity of superoxide dismutase, while it decreased the increased level of malondialdehyde in the lung tissues. Importantly, CGRP treatment significantly decreased the magnitude of the hyperoxia-mediated increase in the expression levels of tumor necrosis factor-α mRNA and transforming growth factor-β 1 protein. In conclusion, the hyperoxia-induced acute lung injury is associated with both oxidative stress and inflammatory responses, and CGRP may ameliorate the hyperoxia-induced lung injury by down-regulating these processes.

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Section: Discussionmentioning

confidence: 99%

Calcitonin Gene-Related Peptide Ameliorates Hyperoxia-Induced Lung Injury in Neonatal Rats

Dang

Yang

Wang

et al. 2012

Tohoku J. Exp. Med.

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“…Electron (40) and confocal (41) microscopic studies in animals have shown specialized epithelial cells together with nerves. Accordingly, it is probable that at least a proportion of these cells are innervated by vagal afferents (42). Although the formation of cytoneural junctions is generally regarded as unlikely, the close association of fibers with epithelial cells is strongly suggestive of the presence of afferent signaling (43).…”

Section: Observationsmentioning

confidence: 99%

Morphologic Characterization of Nerves in Whole-Mount Airway Biopsies

West

Canning²,

Merlo‐Pich

et al. 2015

Am J Respir Crit Care Med

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Rationale: Neuroplasticity of bronchopulmonary afferent neurons that respond to mechanical and chemical stimuli may sensitize the cough reflex. Afferent drive in cough is carried by the vagus nerve, and vagal afferent nerve terminals have been well defined in animals. Yet, both unmyelinated C fibers and particularly the morphologically distinct, myelinated, nodose-derived mechanoreceptors described in animals are poorly characterized in humans. To date there are no distinctive molecular markers or detailed morphologies available for human bronchopulmonary afferent nerves.Objectives: Morphologic and neuromolecular characterization of the afferent nerves that are potentially involved in cough in humans.Methods: A whole-mount immunofluorescence approach, rarely used in human lung tissue, was used with antibodies specific to protein gene product 9.5 (PGP9.5) and, for the first time in human lung tissue, 200-kD neurofilament subunit. Measurements and Main Results:We have developed a robust technique to visualize fibers consistent with autonomic and C fibers and pulmonary neuroendocrine cells. A group of morphologically distinct, 200-kD neurofilament-immunopositive myelinated afferent fibers, a subpopulation of which did not express PGP9.5, was also identified.Conclusions: PGP9.5-immunonegative nerves are strikingly similar to myelinated airway afferents, the cough receptor, and smooth muscle-associated airway receptors described in rodents. These have never been described in humans. Full description of human airway nerves is critical to the translation of animal studies to the clinical setting.

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“…The general speciWcity of the primary antibodies for their respective antigens was described before in rat lungs (Brouns et al 2000(Brouns et al , 2002a(Brouns et al , b, 2003(Brouns et al , 2006aPintelon et al 2003). Due to the en bloc dissection and sectioning of intrathoracic organs, the esophagus was typically included as a positive control for VGLUT1 (Kraus et al 2007), VGLUT2 (Raab and Neuhuber 2003) and P2X 2 receptor immunostaining (Castelucci et al 2003;Raab and Neuhuber 2005).…”

Section: Control Experiments For the Immunohistochemical Proceduresmentioning

confidence: 99%

“…These vagal sensory nerve Wbers were shown to be myelinated and capsaicin insensitive, and express vesicular glutamate transporter (VGLUT) 1 and 2 (VGLUTs are transmembrane proteins that load glutamate into synaptic vesicles), the calcium-binding protein calbindin D-28 k (CB), and P2X 3 ATP receptors or Na + /K + -ATPase 3 (Brouns et al 2000(Brouns et al , 2006a. Apart from the vagal innervation, neurons in thoracic dorsal root ganglia (DRG) (Springall et al 1987, own unpublished observations) appear to give rise to an unmyelinated capsaicinsensitive C-Wber-like calcitonin gene-related peptide (CGRP)-and substance P (SP)-immunoreactive (-ir) nerve Wber population that does not penetrate the epithelium, but rather forms a nervous plexus at the basal pole of rat NEBs (Cadieux et al 1986;Shimosegawa and Said 1991;Adriaensen et al 2003;Brouns et al 2003;Van Genechten et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Neurochemical pattern of the complex innervation of neuroepithelial bodies in mouse lungs

Brouns

Öztay

Pintelon

et al. 2008

Histochem Cell Biol

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As best characterized for rats, it is clear that pulmonary neuroepithelial bodies (NEBs) are contacted by a plethora of nerve fiber populations, suggesting that they represent an extensive group of multifunctional intraepithelial airway receptors. Because of the importance of genetically modified mice for functional studies, and the current lack of data, the main aim of the present study was to achieve a detailed analysis of the origin and neurochemical properties of nerve terminals associated with NEBs in mouse lungs. Antibodies against known selective markers for sensory and motor nerve terminals in rat lungs were used on lungs from control and vagotomized mice of two different strains, i.e., Swiss and C57-Bl6. NEB cells were visualized by antibodies against either the general neuroendocrine marker protein gene-product 9.5 (PGP9.5) or calcitonin gene-related peptide (CGRP). Thorough immunohistochemical examination of NEB cells showed that some of these NEB cells also exhibit calbindin D-28 k (CB) and vesicular acetylcholine transporter (VAChT) immunoreactivity (IR). Mouse pulmonary NEBs were found to receive intraepithelial nerve terminals of at least two different populations of myelinated vagal afferents: (1) Immunoreactive (ir) for vesicular glutamate transporters (VGLUTs) and CB; (2) expressing P2X(2) and P2X(3) ATP receptors. CGRP IR was seen in varicose vagal nerve fibers and in delicate non-vagal fibers, both in close proximity to NEBs. VAChT immunostaining showed very weak IR in the NEB-related intraepithelial vagal sensory nerve terminals. nNOS- or VIP-ir nerve terminals could be observed at the base of pulmonary NEBs. While a single NEB can be contacted by multiple nerve fiber populations, it was clear that none of the so far characterized nerve fiber populations contacts all pulmonary NEBs. The present study revealed that mouse lungs harbor several populations of nerve terminals that may selectively contact NEBs. Although at present the physiological significance of the innervation pattern of NEBs remains enigmatic, it is likely that NEBs are receptor-effector end-organs that may host complex and/or multiple functional properties in normal airways. The neurochemical information on the innervation of NEBs in mouse lungs gathered in the present study will be essential for the interpretation of upcoming functional data and for the study of transgenic mice.

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Sensory receptors in the airways: neurochemical coding of smooth muscle-associated airway receptors and pulmonary neuroepithelial body innervation

Cited by 43 publications

References 29 publications

Calcitonin Gene-Related Peptide Ameliorates Hyperoxia-Induced Lung Injury in Neonatal Rats

Calcitonin Gene-Related Peptide Ameliorates Hyperoxia-Induced Lung Injury in Neonatal Rats

Morphologic Characterization of Nerves in Whole-Mount Airway Biopsies

Neurochemical pattern of the complex innervation of neuroepithelial bodies in mouse lungs

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