Animal Models: Other Challenges and Mediators

Viral infection can cause dysfunction of M₂ muscarinic receptors (of parasympathetic nerves) leading to increased release of acetylcholine and airway hyperreactivity. The role of CD8⁺ T cells in airway hyperreactivity and M₂ receptor dysfunction induced by parainfluenza virus infection was studied by Adamko and coworkers in guinea pigs. Depletion of CD8⁺ T cells prevented the M₂ receptor dysfunction and airway hyperreactivity in guinea pigs sensitized to ovalbumin; it had no effect in nonsensitized guinea pigs. Sensitization increased the number of eosinophils in close relation to airway nerves. (When activated, the airway nerves release major basic protein, which binds to and blocks the M₂ muscarinic receptors). Viral infection decreased the number of tissue eosinophils, likely reflecting degranulation; this effect was prevented by depletion of CD8⁺ T cells. The authors conclude that CD8⁺ T cells play a role in the virus-induced dysfunction of M₂ muscarinic receptors and airway hyperreactivity in ovalbumin-sensitized guinea pigs (but not in nonsensitized guinea pigs), secondary to degranulation of eosinophils near the airway nerves.

Induction of anesthesia with a single volatile anesthetic can cause cough, secretion, and airway obstruction in children. In 4- to 5-week-old guinea pigs anesthetized with urethane, Mutoh and Tsubone studied the effect of two volatile anesthetics, halothane and sevoflurane, on the responsiveness of C-fiber afferents recorded from the internal carotid branch of the superior laryngeal nerve. Halothane caused twice as much responsiveness to capsaicin (injected into the left atrium or delivered by nebulization to the larynx) or laryngeal hyperinflation as did sevoflurane; baseline activity was unaffected. The authors conclude that the sensitivity of C-fiber afferents to chemical and mechanical stimuli in young guinea pigs is enhanced more by halothane than by sevoflurane.

Dopamine D₂–like receptors are known to inhibit the activity of dopaminergic neurons in the ventral tegmental area of the brain, and stimulation of dopamine D₂–like receptors attenuates the afferent responses of the carotid chemoreceptors to hypoxia. Lin and coworkers asked, "Does activation of dopamine D₂–like receptors inhibit the hyperresponsiveness of pulmonary C fibers induced by inflammatory mediators?". In anesthetized, open-chest rats, a constant infusion of prostaglandin E₂ significantly enhanced the response of C-fiber afferents to capsaicin injection. Pretreatment with quinpirole, an antagonist of D₂-like receptors, caused marked attenuation of the hyperresponsiveness to capsaicin at 20 minutes, and the inhibitory action persisted for more than 90 minutes. The effect of quinpirole was dose-dependent. The effect was antagonized by pretreatment with domperidone, a D₂-like receptor antagonist (administered 10 minutes before quinpirole). In separate experiments, prostaglandin E₂ augmented the response of C fibers to injections of phenyl biguanide and lactic acid, and constant-pressure lung inflation; these potentiating responses were also reduced by quinpirole. The effect of quinpirole was equally effective in inhibiting the increase in excitability of pulmonary C fibers induced by alveolar hypercapnia or a constant infusion of adenosine. The authors conclude that activation of dopamine D₂–like receptors attenuates the hyperresponsiveness of pulmonary C fibers to both chemical stimuli and lung inflation.

To determine the role of neurokinins in the development of hyperventilation-induced bronchoconstriction, Freed and coworkers used bronchoscopy to measure peripheral airway resistance and the production and release of eicosanoids in anesthetized dogs. Pretreatment with antagonists of neurokinin-1 and neurokinin-2 receptors reduced hyperventilation-induced bronchoconstriction by about 50%; the combined antagonism virtually abolished the airway reactivity to neurokinin A, partially reduced the response to substance P, and had little effect on the response to hypertonic saline. Blockade of the neurokinin receptors did not affect cell profiles, prostaglandin D₂, or cysteinyl leukotrienes in bronchoalveolar fluid after hyperventilation. The authors conclude that neurokinin receptors modulate hyperventilation-induced bronchoconstriction and do so in part via eicosanoid production and release.

In mice, Martin and coworkers investigated the effect of exposure to chlorine gas on airway inflammation and hyperresponsiveness, and the role of oxidative mechanisms in the response. A 5-minute exposure to 400 or 800 ppm of chlorine caused increases in airway hyperresponsiveness 24 hours later. Responsiveness after inhaling 400 ppm of chlorine returned to normal by 2 days, but was again elevated at 7 days. Exposure to 800 ppm caused loss of airway epithelium, patchy alveolar damage, proteinaceous exudates, and inflammatory cells within alveolar walls. Macrophages, granulocytes, epithelial cells, and nitrate/nitrite levels were increased in lung lavage fluid. Expression of inducible nitric oxide synthase was increased, and lung proteins were oxidized. Exposure to 800 ppm was associated with staining of epithelial cells and alveolar macrophages for 3-nitrotyrosine residues. Inhibition of inducible nitric oxide synthase abrogated the changes in responsiveness induced by chlorine. The authors conclude that exposure to chlorine gas causes functional and pathological changes in the airways induced by oxidative stress and that inducible nitric oxide synthase contributes to the airway hyperresponsiveness.

Citations 1-7 of 7 total displayed.

Chlorine-induced Injury to the Airways in Mice

James G. Martin, Holly R. Campbell, Hiroaki Iijima, Denyse Gautrin, Jean-Luc Malo, David H. Eidelman, Qutayba Hamid, and Karim Maghni
Am. J. Respir. Crit. Care Med. 168: 568 -574. First published online as doi:10.1164/rccm.200201-021OC [Abstract] [Full text]  

Activation of Dopamine D₂-like Receptors Attenuates Pulmonary C-Fiber Hypersensitivity in Rats

You Shuei Lin, Qihai Gu, and Lu-Yuan Lee
Am. J. Respir. Crit. Care Med. 167: 1096 -1101. First published online as doi:10.1164/rccm.200210-1171OC [Abstract] [Full text]  

Neurokinins Modulate Hyperventilation-induced Bronchoconstriction in Canine Peripheral Airways

Arthur N. Freed, Sharron McCulloch, Teresa Meyers, and Ryoichi Suzuki
Am. J. Respir. Crit. Care Med. 167: 1102 -1108. First published online as doi:10.1164/rccm.200201-055OC [Abstract] [Full text]  

CD8⁺ T Lymphocytes in Viral Hyperreactivity and M₂ Muscarinic Receptor Dysfunction

Darryl J. Adamko, Allison D. Fryer, Bruce S. Bochner, and David B. Jacoby
Am. J. Respir. Crit. Care Med. 167: 550 -556. First published online as doi:10.1164/rccm.200206-506OC [Abstract] [Full text]  

Hypersensitivity of Laryngeal C-Fibers Induced by Volatile Anesthetics in Young Guinea Pigs

Tatsushi Mutoh and Hirokazu Tsubone
Am. J. Respir. Crit. Care Med. 167: 557 -562. First published online as doi:10.1164/rccm.200207-768BC [Abstract] [Full text]  

Do Complex Conditions Require Complex Treatment?

Mark Inman
Am. J. Respir. Crit. Care Med. 167: 6. [Full text]  

Differential Regulation by Glucocorticoid of Interleukin-13–induced Eosinophilia, Hyperresponsiveness, and Goblet Cell Hyperplasia in Mouse Airways

Atsuko Kibe, Hiromasa Inoue, Satoru Fukuyama, Kentaro Machida, Koichiro Matsumoto, Hiroshi Koto, Tomomi Ikegami, Hisamichi Aizawa, and Nobuyuki Hara
Am. J. Respir. Crit. Care Med. 167: 50-56. [Abstract] [Full text]