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Proinflammatory Peptides in Sensory Nerves of the Airways
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Peter Baluk, Donald M. McDonald
The possible upregulation of tachykinins has attracted attention as a mechanism of regulating the response to stimuli in conditions of chronic inflammation and pain (279,280). Sensory nerves, like sympathetic nerves, depend for their survival on nerve growth factor (NGF), and other neurotrophins produced by the target cells that they innervate (281). Cytokines also regulate the expression of substance P (282). Chronic inflammation or pain, such as the injection of formalin into the hindpaws of rats, can increase the synthesis of neurokinins in the spinal cord or dorsal root ganglia (283,284). Guinea pigs chronically exposed to cigarette smoke had increased amounts of CGRP in their lower airways (285), and rats chronically exposed to sulfur dioxide had threefold higher concentrations of substance P in their tracheas (286). The mechanisms for these increases are not yet clear. However, one possibility is that chronic stimulation and transmitter release may necessitate and facilitate transmitter synthesis. Sensory nerves, like sympathetic nerves, depend for their survival on nerve growth factor (NGF), other neurotrophins, and cytokines produced by the target cells they innervate (281,282,287). The chronic presence of other inflammatory mediators, such as bradykinin and cyclooxygenase products (288), or infections can cause sensory hyperalgesia, so that the threshold for release of peptides is decreased. For example, plasma leakage can be induced in the airways of rats with Mycoplasma pulmonis infections with much lower doses of capsaicin than required in pathogen-free rats (289).
Sensory and Inflammatory Peptide Receptors in Airways
Published in Devendra K. Agrawal, Robert G. Townley, Inflammatory Cells and Mediators in Bronchial Asthma, 2020
SP is localized to unmyelinated sensory nerves (C-fibers) in airways.5–7 In rodents there is a rich innervation of SP-immunoreactive nerves which are found in close association with airway epithelium and sometimes penetrate the epithelial layer. In addition, SP-immunoreactive nerves are also seen in airway smooth muscle, around submucosal glands, around submucosal blood vessels, and in relation to parasympathetic ganglia. In human airways, SP innervation is much less prominent7 and in some studies has not been found.8 This may be related to the fact that human airways have usually been obtained at surgery for lung carcinoma from older smokers in whom these nerves may be depleted. Preliminary studies have shown that in asthmatic airways there may be a prominent SP innervation, suggesting that chronic inflammation may lead to proliferation of these nerves. Recently, three other tachykinins have been identified in the mammalian nervous system. Neurokinin A (NKA), which was previously known as substance K, is coded by the same gene as SP9 and is often colocalized with it in sensory nerves. NKA is localized to sensory nerves in animal and human airways.10 Neuropeptide K is an N-terminally extended form of NKA which is also coded by the same gene. NKB (previously known as neuromedin K) is localized predominantly to the brain and is coded by a separate gene.11 It has not yet been reported in the lung.
Epithelial Function and Airway Responsiveness
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Roy G. Goldie, Janet M. H. Preuss
The tachykinins are potent bronchoconstrictors of isolated airway preparations from several species including humans in which bronchospasm appears to be via an NK2 receptor.114–116 SP induces mucus secretion in animal and human airways in vitro117–119 and may be also responsible for e-NANC bronchoconstriction.120–122 Exogenous neurokinins increase microvascular permeability in rat and guinea pig airways and may also mediate neurogenic leakage.11,123 The ability of the tachykinins to modulate responses of inflammatory cells suggests that they have a role as immunomodulators.124,125
Blocking SP/NK1R signaling improves spinal cord hemisection by inhibiting the release of pro-inflammatory cytokines in rabbits
Published in The Journal of Spinal Cord Medicine, 2023
Yuehuan Zheng, Nannan Wang, Zhe Chen, Liqiang Shi, Xiangyang Xu
The blood-spinal cord barrier is destroyed immediately after SCI, and the vascular permeability increases continuously for 7–8 weeks after the injury,5 allowing high-moleculary-weight inflammatory mediators to enter the central nervous system to exert neurotoxicity and impair neuronal function.6 Tachykinin is involved in the regulation of sensory and emotional responses and various neuronal signaling pathways.7 Substance P (SP), neurokinin A and neurokinin B are the three main tachykinins in mammals.7 Studies have shown that SP, a precursor neuropeptide, plays an important role in nociceptive activity at the spinal cord level in response to peripheral inflammation and nociceptive stimuli.8 In addition, SP can also induce increased microvascular permeability, vasodilatation and tissue edema, and is considered to be a key mediator of neurogenic inflammation.9 SP preferentially activates neurokinin 1 receptor (NK1R).10 The inhibitory effect of NK-1R antagonist on inflammatory response has been confirmed in spinal neuron,11 microglia12 and macrophages.13 Therefore, the SP-NK1R axis played an important role in the regulation of inflammation.
Pharmacological Treatment of Generalised Anxiety Disorder: Current Practice and Future Directions
Published in Expert Review of Neurotherapeutics, 2023
Harry A. Fagan, David S. Baldwin
The tachykinin system is a neuropeptide system involved in a variety of physiological functions [112]. It consists of several neuropeptides and three neurokinin receptors (1–3) [112]. Substance P (SP) is widely expressed throughout the brain and preferentially binds the neurokinin 1 receptor (NK1R) [113]. SP and NK1R have been implicated in the stress response and anxiety in animal studies [113]. NK1R antagonists have been developed and showed promise in animal models of anxiety and were translated into clinical populations, but without success. One RCT compared the NK1R antagonist L-759274 with lorazepam and placebo treatment over 6 weeks in patients with GAD [114]. No difference in HAM-A score was noted between L-759274 and placebo at the end of the treatment period [114]. The additional NK1R antagonists LY686017 and GR205171 did not differentiate from placebo treatment in the treatment of SAD and PTSD, respectively, [115,116]. To our knowledge, no further studies using tachykinin-modulating agents in anxiety disorders, are currently ongoing.
Neuroendocrine control of lipid metabolism: lessons from C. elegans
Published in Journal of Neurogenetics, 2020
A remarkable feature of the tachykinin neuroendocrine pathway is that all of the neuronal effects on global fat metabolism occur without appreciable changes in food intake (Hussey et al., 2017; Hussey et al., 2018; Noble et al., 2013; Palamiuc et al., 2017; Srinivasan et al., 2008; Witham et al., 2016), suggesting that the regulation of body fat is indeed distinct from food intake alone. The tachykinin neuropeptides, first defined by Substance P were originally identified more than 80 years ago (Guillemin, 2013), but have not previously been associated with lipid metabolism. The tachykinin peptides and receptors have been predominantly associated with inflammation in mammals (Steinhoff, von Mentzer, Geppetti, Pothoulakis, & Bunnett, 2014), which has mechanistic ties to metabolic dysfunction, however the role of tachykinins in mammalian metabolism remain unknown.