Pulmonary chemoreflex responses are potentiated by tumor necrosis factor-alpha in mice

Lin, Ruei‐Lung; Lin, Yu‐Jung; Geer, Marcus; Lee, Lu-Yuan

doi:10.1152/japplphysiol.01301.2012

Cited by 13 publications

(22 citation statements)

References 42 publications

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“…For example, pronounced increases in the plasma levels of tumor necrosis factor-␣ (TNF-␣), interleukin (IL)-1, IL-6, and IL-10 have been reported in the studies when hemorrhage of similar intensity and duration of hypotension as that in our study was induced (1). Some of these cytokines such as TNF-␣ and IL-1␤ are known to exert potent stimulatory and/or sensitizing effects on vagal pulmonary C-fiber afferents (16,22,31).…”

Section: Discussionsupporting

confidence: 66%

Hemorrhagic hypotension-induced hypersensitivity of vagal pulmonary C-fibers to chemical stimulation and lung inflation in anesthetized rats

Lin

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Lin RL, Lin YJ, Xu F, Lee LY. Hemorrhagic hypotensioninduced hypersensitivity of vagal pulmonary C-fibers to chemical stimulation and lung inflation in anesthetized rats. Am J Physiol Regul Integr Comp Physiol 308: R605-R613, 2015. First published January 14, 2015 doi:10.1152/ajpregu.00424.2014.-This study was carried out to investigate whether hemorrhagic hypotension (HH) altered the sensitivity of vagal pulmonary C-fibers. The fiber activity (FA) of single vagal pulmonary C-fiber was continuously recorded in anesthetized rats before, during, and after HH was induced by bleeding from the femoral arterial catheter into a blood reservoir and lowering the mean systemic arterial pressure (MSAP) to ϳ40 mmHg for 20 min. Our results showed the following. First, after MSAP reached a steady state of HH, the peak FA response to intravenous injection of capsaicin was elevated by approximately fivefold. The enhanced C-fiber sensitivity continued to increase during HH and sustained even after MSAP returned to baseline during the recovery, but slowly returned to control ϳ20 min later. Second, responses of FA to intravenous injections of other chemical stimulants of pulmonary C-fibers (phenylbiguanide, lactic acid, and adenosine) and a constantpressure lung hyperinflation were all significantly potentiated by HH. Third, infusion of sodium bicarbonate alleviated the systemic acidosis during HH, and it also attenuated, but did not completely prevent, the HH-induced C-fiber hypersensitivity. In conclusion, the pulmonary C-fiber sensitivity was elevated during HH, probably caused by the endogenous release of chemical substances (e.g., lactic acid) that were produced by tissue ischemia during HH. This enhanced C-fiber sensitivity may heighten the pulmonary protective reflexes mediated through these afferents (e.g., cough, J reflex) during hemorrhage when the body is more susceptible to other hazardous insults and pathophysiological stresses.hemorrhage; pulmonary; C-fiber; hypoxia; hypersensitivity VAGAL BRONCHOPULMONARY C-fibers represent ϳ75% of the vagal afferents arising from the lung and airways (17). These unmyelinated afferents innervate the entire respiratory tract and play an important role in regulating the respiratory functions under various physiological and pathophysiological conditions (5, 21). Activation of these afferents elicits centrally mediated protective reflex responses via the cholinergic pathway, which include laryngeal closure, bronchoconstriction and airway hypersecretion, accompanied by cough, airway irritation, dyspneic sensation, and J reflex (5, 21). Activation of these sensory nerves can also trigger release of tachykinins and calcitonin gene-related peptide from the sensory terminals, which can act on a number of effector cells in the respiratory tract (e.g., smooth muscles, cholinergic ganglia, mucous glands, immune cells), and elicit the local "axon reflexes" such as bronchoconstriction, protein extravasation, and inflammatory cell chemotaxis (5, 18, 21).Tissue ischemia is known to activate C-fib...

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Section: Discussionsupporting

confidence: 66%

Hemorrhagic hypotension-induced hypersensitivity of vagal pulmonary C-fibers to chemical stimulation and lung inflation in anesthetized rats

Lin

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…An increase in the tissue temperature can increase the metabolic rate and production of CO 2 and hydrogen ion locally in the airway and lung tissue, which may induce the nonspecific hypersensitivity of pulmonary C-fibers (13). Acute hyperthermia can also elevate the levels of several inflammatory mediators such as arachidonic acid metabolites [e.g., prostaglandin E 2 (PGE 2 )] (6) and pro-inflammatory cytokines [e.g., tumor necrosis factor-␣ (TNF-␣)] in the tissue and blood (5); and the sensitizing effects of PGE 2 and TNF-␣ on bronchopulmonary C-fibers are well documented (18,23,30). Furthermore, it has been shown that increasing temperature to ϳ42°C shifts the TRPV1 channel activation curve from a nonphysiological positive voltage range toward the negative potential in a physiologically relevant voltage range (44).…”

Section: Discussionmentioning

confidence: 99%

Hypersensitivity of vagal pulmonary C-fibers induced by increasing airway temperature in ovalbumin-sensitized rats

Lin¹,

Lin²,

Khosravi

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Our recent study has shown that hyperventilation of humidified warm air (HWA) triggered cough and reflex bronchoconstriction in patients with mild asthma. We suggested that a sensitizing effect on bronchopulmonary C-fibers by increasing airway temperature was involved, but direct evidence was lacking. This study was carried out to test the hypothesis that HWA enhances the pulmonary C-fiber sensitivity in Brown-Norway rats sensitized with ovalbumin (Ova). In anesthetized rats, isocapnic hyperventilation of HWA for 3 min rapidly elevated airway temperature to a steady state of 41.7°C. Immediately after the HWA challenge, the baseline fiber activity (FA) of pulmonary C-fibers was markedly elevated in sensitized rats, but not in control rats. Furthermore, the response of pulmonary C-fibers to right atrial injection of capsaicin in sensitized rats was significantly higher than control rats before the HWA challenge, and the response to capsaicin was further amplified after HWA in sensitized rats (ΔFA = 4.51 ± 1.02 imp/s before, and 9.26 ± 1.74 imp/s after the HWA challenge). A similar pattern of the HWA-induced potentiation of the FA response to phenylbiguanide, another chemical stimulant of C-fibers, was also found in sensitized rats. These results clearly demonstrated that increasing airway temperature significantly elevated both the baseline activity and responses to chemical stimuli of pulmonary C-fibers in Ova-sensitized rats. In conclusion, this study supports the hypothesis that the increased excitability of these afferents may have contributed to the cough and reflex bronchoconstriction evoked by hyperventilation of HWA in patients with asthma.

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“…The animal preparation and experimental methods were described in details by Lin et al [27]. Briefly, after mice were anesthetized by isoflurane inhalation, a small (~0.5 cm) mid-line incision was made on the ventral neck skin to expose the trachea.…”

Section: Airway Inflammation Induced By Tnfαmentioning

confidence: 99%

“…Results showed that the total number of leukocyte cells was significantly higher in the WT mice 1 day after a treatment with TNFα than that in each of the other four groups of mice. No significant difference was found between these four other groups [27]. More strikingly, the percentages of eosinophils and neutrophils in the TNFα (1 day) group were >15 folds higher than that in naïve, Veh, TNFα (7 days), and TNF −/− +TNFα groups, and no significant difference was found in either eosinophils or neutrophils between these four other groups [27].…”

Section: Airway Inflammation Induced By Tnfαmentioning

confidence: 99%

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Sustained sensitizing effects of tumor necrosis factor alpha on sensory nerves in lung and airways

Lin

Khosravi

et al. 2017

Pulmonary Pharmacology & Therapeutics

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Tumor necrosis factor alpha (TNFα) plays a significant role in the pathogenesis of airway inflammatory diseases. Inhalation of aerosolized TNFα induced airway hyperresponsiveness accompanied by airway inflammation in healthy human subjects, but the underlying mechanism is not fully understood. We recently reported a series of studies aimed to investigate if TNFα elevates the sensitivity of vagal bronchopulmonary sensory nerves in a mouse model; these studies are summarized in this mini-review. Our results showed that intratracheal instillation of TNFα induced pronounced airway inflammation 24 hours later, as illustrated by infiltration of eosinophils and neutrophils and the release of inflammatory mediators and cytokines in the lung and airways. Accompanying these inflammatory reactions, the sensitivity of vagal pulmonary C-fibers and silent rapidly adapting receptors to capsaicin, a selective agonist of transient receptor potential vanilloid type 1 receptor, was markedly elevated after the TNFα treatment. A distinct increase in the sensitivity to capsaicin induced by TNFα was also observed in isolated pulmonary sensory neurons, suggesting that the sensitizing effect is mediated primarily through a direct action of TNFα on these neurons. Furthermore, the same TNFα treatment also induced a lingering (> 7days) cough hyperresponsiveness to inhalation challenge of NH3 in awake mice. Both the airway inflammation and the sensitizing effect on pulmonary sensory neurons caused by the TNFα treatment were abolished in the TNF-receptor double homozygous mutant mice, indicating the involvement of TNF-receptor activation. These findings suggest that the TNFα-induced hypersensitivity of vagal bronchopulmonary afferents may be responsible for, at least in part, the airway hyperresponsiveness caused by inhaled TNFα in healthy individuals.

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Pulmonary chemoreflex responses are potentiated by tumor necrosis factor-alpha in mice

Cited by 13 publications

References 42 publications

Hemorrhagic hypotension-induced hypersensitivity of vagal pulmonary C-fibers to chemical stimulation and lung inflation in anesthetized rats

Hemorrhagic hypotension-induced hypersensitivity of vagal pulmonary C-fibers to chemical stimulation and lung inflation in anesthetized rats

Hypersensitivity of vagal pulmonary C-fibers induced by increasing airway temperature in ovalbumin-sensitized rats

Sustained sensitizing effects of tumor necrosis factor alpha on sensory nerves in lung and airways

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