IL-1 Receptors Mediate Persistent, but Not Acute, Airway Hyperreactivity to Ozone in Guinea Pigs

Verhein, Kirsten C.; Jacoby, David B.; Fryer, A.D.

doi:10.1165/rcmb.2008-0045oc

Cited by 24 publications

(27 citation statements)

References 73 publications

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“…Guinea pig in vivo experiments are described in the online supplement (22). Reproducible bronchoconstrictions were induced by electrical stimulation of the vagus nerves (8 V, 15 Hz, 2 ms duration, 3 s on, 40 s off) in anesthetized, paralyzed, and ventilated guinea pigs.…”

Section: In Vivo Guinea Pig Physiologymentioning

confidence: 99%

Toll-like Receptor 7 Rapidly Relaxes Human Airways

Drake

Scott

Proskocil

et al. 2013

Am J Respir Crit Care Med

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Rationale: Toll-like receptors (TLRs) 7 and 8 detect respiratory virus single-stranded RNA and trigger an innate immune response. We recently described rapid TLR7-mediated bronchodilation in guinea pigs. Objectives: To characterize TLR7 expression and TLR7-induced airway relaxation in humans and in eosinophilic airway inflammation in guinea pigs. To evaluate the relaxant effects of other TLRs. Methods: Human airway smooth muscle strips were contracted with methacholine in vitro, and responses to TLR7 and TLR8 agonists were assessed. TLR7-mediated nitric oxide production was measured using a fluorescent indicator, and TLR7 expression was characterized using immunofluorescence. TLR7 signaling was also evaluated in ovalbumin-challenged guinea pigs. Measurements and Main Results: The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation of methacholine-contracted human airways in vitro. This was blocked by the TLR7 antagonist IRS661 and by inhibiting nitric oxide production but not by inhibiting prostaglandin production. TLR7 activation markedly increased fluorescence of a nitric oxide detector. TLR7 was expressed on airway nerves, but not airway smooth muscle, implicating airway nerves as the source of TLR7-induced nitric oxide production. TLR7-mediated relaxation persisted in inflamed guinea pigs airways in vivo. The TLR8 agonists polyuridylic acid and polyadenylic acid also relaxed human airways, and this was not blocked by the TLR7 antagonist or by blocking nitric oxide or prostaglandin production. No other TLRs relaxed the airways. Conclusions: TLR7 is expressed on airway nerves and mediates relaxation of human and animal airways through nitric oxide production. TLR7-mediated bronchodilation may be a new therapeutic strategy in asthma.Keywords: Toll-like receptor 7; imiquimod; nitric oxide; asthma; nerve Toll-like receptor (TLR) 7 is a pattern recognition receptor in the lungs (1-3) that detects single-stranded RNA genomes, common to many respiratory viruses (4). Respiratory viruses cause airway hyperreactivity (an abnormal tendency to contract) (5, 6) and asthma exacerbations (7). A role for TLR7 in the development of virus-induced airway hyperreactivity has been proposed, because TLR7 activation causes a proinflammatory type 1 T-helper cell (Th1) immune response (8) and because TLR7 polymorphisms have been associated with asthma (9). In patients with asthma, however, TLR7 responses were reduced (10). Furthermore, in mouse models of allergic airway inflammation, the TLR7 imidazoquinoline agonists imiquimod (R837) and resiquimod (R848) reduced airway hyperreactivity, airway eosinophilia, goblet cell hyperplasia, and smooth muscle hypertrophy (11-14), whereas TLR7 knockout mice were prone to the development of asthma-like airway pathology after pneumovirus infection (15). These studies suggest that TLR7 may be protective against the development of allergic type 2 T-helper cell airway inflammation, possibly by altering the Th1 versus Th2 immune balance (16). Similarly, a TLR7 agonist is currently i...

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Section: In Vivo Guinea Pig Physiologymentioning

confidence: 99%

Toll-like Receptor 7 Rapidly Relaxes Human Airways

Drake

Scott

Proskocil

et al. 2013

Am J Respir Crit Care Med

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“…In experimental models, administration of TNF-␣ or IL-1␤ enhances airway reactivity (29,57). Conversely, blocking TNF-␣ or IL-1␤ with specific antagonists prevents airway hyperreactivity caused by antigen and other environmental triggers, such as ozone (35,49,56). TNF-␣ and IL-1␤ and other macrophage factors can decrease M2 muscarinic receptor function or expression (35).…”

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confidence: 99%

Macrophage TNF-α mediates parathion-induced airway hyperreactivity in guinea pigs

Proskocil

Bruun

Jacoby

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Organophosphorus pesticides (OPs) are implicated in human asthma. We previously demonstrated that, at concentrations that do not inhibit acetylcholinesterase activity, the OP parathion causes airway hyperreactivity in guinea pigs as a result of functional loss of inhibitory M2 muscarinic receptors on parasympathetic nerves. Because macrophages are associated with asthma, we investigated whether macrophages mediate parathion-induced M2 receptor dysfunction and airway hyperreactivity. Airway physiology was measured in guinea pigs 24 h after a subcutaneous injection of parathion. Pretreatment with liposome-encapsulated clodronate induced alveolar macrophage apoptosis and prevented parathion-induced airway hyperreactivity in response to electrical stimulation of the vagus nerves. As determined by qPCR, TNF-α and IL-1β mRNA levels were increased in alveolar macrophages isolated from parathion-treated guinea pigs. Parathion treatment of alveolar macrophages ex vivo did not significantly increase IL-1β and TNF-α mRNA but did significantly increase TNF-α protein release. Consistent with these data, pretreatment with the TNF-α inhibitor etanercept but not the IL-1β receptor inhibitor anakinra prevented parathion-induced airway hyperreactivity and protected M2 receptor function. These data suggest a novel mechanism of OP-induced airway hyperreactivity in which low-level parathion activates macrophages to release TNF-α-causing M2 receptor dysfunction and airway hyperreactivity. These observations have important implications regarding therapeutic approaches for treating respiratory disease associated with OP exposures.

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“…Three days after ozone exposure, hyperreactivity is no longer mediated by eosinophils (66) but is blocked by an antagonist to IL-1␤ receptors (56,66). Here, we show that the sustained hyperreactivity 3 days after a single exposure to ozone is also inhibited by pretreatment with AbNGF, which had no effect on hyperreactivity 1 day after ozone (Fig.…”

Section: Discussionmentioning

confidence: 66%

“…neural plasticity; pollution; tachykinin receptors EXPOSURE TO OZONE INDUCES airway hyperreactivity in humans (15,44) and animals (50,56) that occurs immediately after exposure and lasts several days. Acute, ozone-induced hyperreactivity is mediated by release of major basic protein from eosinophils resident in the lungs (65).…”

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confidence: 99%

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Three days after a single exposure to ozone, the mechanism of airway hyperreactivity is dependent on substance P and nerve growth factor

Verhein¹,

Hazari

Moulton

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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Ozone causes persistent airway hyperreactivity in humans and animals. One day after ozone exposure, airway hyperreactivity is mediated by release of eosinophil major basic protein that inhibits neuronal M(2) muscarinic receptors, resulting in increased acetylcholine release and increased smooth muscle contraction in guinea pigs. Three days after ozone, IL-1β, not eosinophils, mediates ozone-induced airway hyperreactivity, but the mechanism at this time point is largely unknown. IL-1β increases NGF and the tachykinin substance P, both of which are involved in neural plasticity. These experiments were designed to test whether there is a role for NGF and tachykinins in sustained airway hyperreactivity following a single ozone exposure. Guinea pigs were exposed to filtered air or ozone (2 parts per million, 4 h). In anesthetized and vagotomized animals, ozone potentiated vagally mediated airway hyperreactivity 24 h later, an effect that was sustained over 3 days. Pretreatment with antibody to NGF completely prevented ozone-induced airway hyperreactivity 3 days, but not 1 day, after ozone and significantly reduced the number of substance P-positive airway nerve bundles. Three days after ozone, NK(1) and NK(2) receptor antagonists also blocked this sustained hyperreactivity. Although the effect of inhibiting NK(2) receptors was independent of ozone, the NK(1) receptor antagonist selectively blocked vagal hyperreactivity 3 days after ozone. These data confirm mechanisms of ozone-induced airway hyperreactivity change over time and demonstrate 3 days after ozone that there is an NGF-mediated role for substance P, or another NK(1) receptor agonist, that enhances acetylcholine release and was not present 1 day after ozone.

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IL-1 Receptors Mediate Persistent, but Not Acute, Airway Hyperreactivity to Ozone in Guinea Pigs

Cited by 24 publications

References 73 publications

Toll-like Receptor 7 Rapidly Relaxes Human Airways

Toll-like Receptor 7 Rapidly Relaxes Human Airways

Macrophage TNF-α mediates parathion-induced airway hyperreactivity in guinea pigs

Three days after a single exposure to ozone, the mechanism of airway hyperreactivity is dependent on substance P and nerve growth factor

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