Review
Sensing pulmonary oxidative stress by lung vagal afferents

https://doi.org/10.1016/j.resp.2011.05.003Get rights and content

Abstract

Oxidative stress in the bronchopulmonary airways can occur through a variety of inflammatory mechanisms and also following the inhalation of environmental pollutants. Oxidative stress causes cellular dysfunction and thus mammals (including humans) have developed mechanisms for detecting oxidative stress, such that defensive behavior and defensive biological mechanisms can be induced to lessen its potential damage. Vagal sensory nerves innervating the airways play a critical role in the detection of the microenvironment in the airways. Oxidative stress and associated compounds activate unmyelinated bronchopulmonary C-fibers, initiating action potentials in these nerves that conduct centrally to evoke unpleasant sensations (e.g. urge to cough, dyspnea, chest-tightness) and to stimulate/modulate reflexes (e.g. cough, bronchoconstriction, respiratory rate, inspiratory drive). This review will summarize the published evidence regarding the mechanisms by which oxidative stress, reactive oxygen species, environmental pollutants and lipid products of peroxidation activate bronchopulmonary C-fibers. Evidence suggests a key role for transient receptor potential ankyrin 1 (TRPA1), although transient receptor potential vanilloid 1 (TRPV1) and purinergic P2X channels may also play a role. Knowledge of these pathways greatly aids our understanding of the role of oxidative stress in health and disease and represents novel therapeutic targets for diseases of the airways.

Introduction

Oxidation of phospholipids, proteins and nucleic acids by reactive oxygen species (ROS) causes cellular dysfunction and thus oxidative stress can be considered a threat to the organism (Karihtala and Soini, 2007). Multicellular organisms have developed defensive systems that can specifically detect noxious stimuli and enact defensive cellular responses and behavior. Sensory (afferent) nerves are the initial part of this defense mechanism. Afferent nerves project nerve terminals into peripheral tissue where, through the activation of specific nerve terminal proteins (ion channels), they detect specific stimuli and relay such information to the central nervous system (CNS) in the form of action potentials. In the case of the large airways and lungs, the afferent innervation comes largely from the vagus nerve, and their activation can cause cough, dyspnea, changes in breathing control, decreased inspiratory capacity, bronchospasm and hypersecretion. In this review, we will summarize the mechanisms by which oxidative stress is detected by vagal airway sensory nerves.

The phrase ‘oxidative stress’ defines a state in which there is a misbalance in the redox environment. This can be induced in two ways: by increasing the levels of pro-oxidants (e.g. ROS) or by decreasing the levels of anti-oxidant defenses (e.g. cytosolic glutathione) (Karihtala and Soini, 2007). In general terms electrophilic pro-oxidants accept electrons from nucleophilic biological compounds (e.g. molecules with –OH or –SH groups). Examples of ROS include superoxide radical (O2), hydroxyl radical, nitric oxide radical, hydrogen peroxide (H2O2) and ozone (O3). The redox potential of ROS varies between chemical species and in biological tissue this tends to negatively correlate with half-life, e.g. the hydroxyl radical is considered the most reactive radical in biology and has a half-life of approximately 1 ns, whereas H2O2 is far less reactive and (unless broken down by catalase) has a half-life that is measured in h/days. In addition to their direct oxidant properties, ROS can cause the production (via a self-propagating lipid peroxidation reaction) of a host of compounds with electrophilic reactive alpha–beta unsaturated carbonyl groups that have many of the same chemical properties (Blair, 2006).

The airways are subjected to oxidative stress derived from two separate sources: inhalation of exogenous irritants and endogenous inflammation. Oxidative stress can be induced directly by inhaled irritants (e.g. electrophilic aldehydes in cigarette smoke, diisocyanates from the manufacture of polyurathane), downstream of ROS production (metal ions and quinones in particulate matter induces O2 production), or downstream of ROS propagation (e.g. O3 induces O2 and H2O2 production and lipid peroxidation). The initial step in the majority of endogenous ROS production is the synthesis of O2, largely through the actions of NADPH oxidase, xanthine oxidase and through inherent (although mild in basal conditions) inefficiencies in mitochondrial electron transfer. Inflammation in the airways causes substantial ROS production and this is largely due to NADPH oxidase activity in activated granulocytes, although evidence suggests mitochondria in airway cells also contribute subsequent to their inflammation-induced dysfunction (Mabalirajan et al., 2008, Mabalirajan et al., 2009, Mabalirajan et al., 2010). ROS and biomarkers for ROS production (e.g. H2O2, isoprostanes, nitrotyrosine residues) are found in lung samples from individuals with asthma and chronic obstructive pulmonary disease (COPD) (Kharitonov and Barnes, 2004, Kirkham and Rahman, 2006, Nadeem et al., 2008) or individuals following exposure to inhalation irritants such as O3, chlorine, cigarette smoke, particulate matter, diisocyanates, isothiocyanates; and these findings concur with animal models of airway disease (Brown and Burkert, 2002, Comandini et al., 2009, Hazbun et al., 1993, Lin and Thomas, 2010, Rouse et al., 2008, White and Martin, 2010). Precisely how stress contributes to the more complex disease states of inflammation, asthma and COPD is unresolved. Through the oxidation of lipid, protein and nucleic acids, exogenously applied ROS induce a variety of inflammatory pathways (Gloire and Piette, 2009, Valko et al., 2007) which causes in vivo epithelial damage, remodeling, bronchospasm and airway hyperreactivity in various models (Comhair and Erzurum, 2010, Hollingsworth et al., 2007, Kinnula et al., 1995, Li et al., 2008b, North et al., 2011, Uysal and Schapira, 2003). The effect of antioxidants in reducing airway inflammation has been less than impressive, particularly in humans (Nadeem et al., 2008). Further evidence for the contribution of oxidative stress to airway disease can be found in functional polymorphisms of antioxidant defense systems. Polymorphisms that reduce the reserve capacity of glutathione correlate with severity of airway disease and exacerbations (Islam et al., 2009, Polimanti et al., 2010, Reddy et al., 2010, Schroer et al., 2009, Shaheen et al., 2010).

Section snippets

Lower airways innervation

Sensory nerves throughout the mammalian body possess similar cellular structure: a cell body (soma) that contains the nucleus and the vast majority of gene transcription and translation machinery/organelles, a peripheral axonal projection from the soma to its target tissue that ends in the peripheral terminal, and a central axonal projection from the soma to synapses with second order neurons within the CNS. Bronchopulmonary vagal sensory nerves are no exception to this rule: with cell bodies

Activation of airway afferents by oxidative stress

Inhalation of pro-oxidants acutely evoke sensations and changes in lung function, consistent with the activation of airway afferent nerves. Inhalation of H2O2 causes a decrease in respiratory rate in rats and mice (Bessac et al., 2008, Ruan et al., 2003). Inhalation of O3 causes cough, dyspnea, decreased forced expiratory volume in 1 s (FEV1) and decreased inspiratory capacity in humans (Hazucha et al., 1989, Kerr et al., 1975, McDonnell et al., 1999) and O3 modulates respiratory rates and

Conclusions

There is a growing literature demonstrating the selective activation of nociceptive airway afferents with various ROS and productions of oxidative stress. Evidence supporting a role of TRPA1 in these responses is very strong. Results from a plethora of studies now indicate that ROS, regardless of structure, categorically stimulate TRPA1. Furthermore, inhibition of TRPA1 dramatically reduces ROS-induced afferent nerve activation. Whether other ion channels (TRPV1 or P2X) also contribute is more

References (118)

  • P. Kirkham et al.

    Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy

    Pharmacol. Ther.

    (2006)
  • A. Kuhad et al.

    Tocotrienol attenuates oxidative-nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy

    Neuropharmacology

    (2009)
  • L.Y. Lee

    Respiratory sensations evoked by activation of bronchopulmonary C-fibers

    Respir. Physiol. Neurobiol.

    (2009)
  • L.Y. Lee et al.

    Airway irritation and cough evoked by inhaled cigarette smoke: role of neuronal nicotinic acetylcholine receptors

    Pulm. Pharmacol. Ther.

    (2007)
  • N. Li et al.

    The role of oxidative stress in ambient particulate matter-induced lung diseases and its implications in the toxicity of engineered nanoparticles

    Free Radic. Biol. Med.

    (2008)
  • U. Mabalirajan et al.

    l-Arginine reduces mitochondrial dysfunction and airway injury in murine allergic airway inflammation

    Int. Immunopharmacol.

    (2010)
  • L.J. Macpherson et al.

    The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin

    Curr. Biol.

    (2005)
  • S.B. Mazzone et al.

    Central nervous system control of the airways: pharmacological implications

    Curr. Opin. Pharmacol.

    (2002)
  • W.A. Pryor

    How far does ozone penetrate into the pulmonary air/tissue boundary before it reacts?

    Free Radic. Biol. Med.

    (1992)
  • N. Agopyan et al.

    TRPV1 receptors mediate particulate matter-induced apoptosis

    Am. J. Physiol. Lung Cell. Mol. Physiol.

    (2004)
  • D.A. Andersson et al.

    Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress

    J. Neurosci.

    (2008)
  • E. Andre et al.

    Cigarette smoke-induced neurogenic inflammation is mediated by alpha,beta-unsaturated aldehydes and the TRPA1 receptor in rodents

    J. Clin. Invest.

    (2008)
  • E. Andre et al.

    Transient receptor potential ankyrin receptor 1 is a novel target for pro-tussive agents

    Br. J. Pharmacol.

    (2009)
  • C.V. Baker et al.

    Establishing neuronal identity in vertebrate neurogenic placodes

    Development

    (2000)
  • B.F. Bessac et al.

    Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control

    Physiology (Bethesda)

    (2008)
  • B.F. Bessac et al.

    Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases

    FASEB J.

    (2009)
  • B.F. Bessac et al.

    TRPA1 is a major oxidant sensor in murine airway sensory neurons

    J. Clin. Invest.

    (2008)
  • M.A. Birrell et al.

    TRPA1 agonists evoke coughing in guinea-pig and human volunteers

    Am. J. Respir. Crit. Care Med.

    (2009)
  • I.A. Blair

    Endogenous glutathione adducts

    Curr. Drug Metab.

    (2006)
  • W.E. Brown et al.

    Biomarkers of toluene diisocyanate exposure

    Appl. Occup. Environ. Hyg.

    (2002)
  • H.G. Brugsch et al.

    Toluene di-isocyanate (TDI) toxicity

    N. Engl. J. Med.

    (1963)
  • A.I. Caceres et al.

    A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma

    Proc. Natl. Acad. Sci. U.S.A.

    (2009)
  • M.J. Carr et al.

    A role for TRPV1 in bradykinin-induced excitation of vagal airway afferent nerve terminals

    J. Pharmacol. Exp. Ther.

    (2003)
  • M.J. Carr et al.

    Bronchopulmonary afferent nerves

    Respirology

    (2003)
  • M.J. Caterina et al.

    The capsaicin receptor: a heat-activated ion channel in the pain pathway

    Nature

    (1997)
  • Y.L. Chou et al.

    Differential effects of airway afferent nerve subtypes on cough and respiration in anesthetized guinea pigs

    Am. J. Physiol. Regul. Integr. Comp. Physiol.

    (2008)
  • H.H. Chuang et al.

    Oxidative challenges sensitize the capsaicin receptor by covalent cysteine modification

    Proc. Natl. Acad. Sci. U.S.A.

    (2009)
  • H.H. Chuang et al.

    Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition

    Nature

    (2001)
  • C. Coddou et al.

    Reactive oxygen species potentiate the P2X2 receptor activity through intracellular Cys430

    J. Neurosci.

    (2009)
  • J.C. Coleridge et al.

    Afferent vagal C fibre innervation of the lungs and airways and its functional significance

    Rev. Physiol. Biochem. Pharmacol.

    (1984)
  • J.C. Coleridge et al.

    Acute inhalation of ozone stimulates bronchial C-fibers and rapidly adapting receptors in dogs

    J. Appl. Physiol.

    (1993)
  • S.A. Comhair et al.

    Redox control of asthma: molecular mechanisms and therapeutic opportunities

    Antioxid. Redox Signal.

    (2010)
  • P. Dinis et al.

    Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis

    J. Neurosci.

    (2004)
  • O. Faroon et al.

    Acrolein health effects

    Toxicol. Ind. Health

    (2008)
  • R.W. Fuller et al.

    Bronchoconstrictor response to inhaled capsaicin in humans

    J. Appl. Physiol.

    (1985)
  • P. Geppetti et al.

    Ruthenium red, but not capsazepine reduces plasma extravasation by cigarette smoke in rat airways

    Br. J. Pharmacol.

    (1993)
  • E. Ghelfi et al.

    Cardiac oxidative stress and electrophysiological changes in rats exposed to concentrated ambient particles are mediated by TRP-dependent pulmonary reflexes

    Toxicol. Sci.

    (2008)
  • G. Gloire et al.

    Redox regulation of nuclear post-translational modifications during NF-kappaB activation

    Antioxid. Redox Signal.

    (2009)
  • R. Graepel et al.

    4-Oxo-2-nonenal (4-ONE): evidence of TRPA1-dependent and -independent nociceptive and vasoactive responses in vivo

    J. Pharmacol. Exp. Ther.

    (2011)
  • M.E. Hazbun et al.

    Ozone-induced increases in substance P and 8-epi-prostaglandin F2 alpha in the airways of human subjects

    Am. J. Respir. Cell Mol. Biol.

    (1993)
  • Cited by (64)

    • Targeting C-fibers for peripheral acting anti-tussive drugs

      2019, Pulmonary Pharmacology and Therapeutics
      Citation Excerpt :

      There are also numerous endogenous lipid mediators that can bind to and open TRPV1 including certain endocannabinoids and eicosanoids [22]. TRPA1 is perhaps more likely to be activated by chemicals that may present to the airway mucosa [23]. Airway C-fibers are activated by environmental irritants via TRPA1; e.g. ozone, acrolein, saturated aldehydes and isocyanates [24].

    • Pulmonary Irritant Responses: Oxidants and Electrophiles

      2018, Comprehensive Toxicology: Third Edition
    View all citing articles on Scopus

    This paper is part of a special issue entitled “Inflammation and Cardio-Respiratory Control”, guest-edited by Frank L. Powell and Yu Ru Kou.

    View full text