Injury to lung epithelial cells has a role in multiple lung diseases. We previously identified mitsugumin 53 (MG53) as a component of the cell membrane repair machinery in striated muscle cells. Here we show that MG53 also has a physiological role in the lung and may be used as a treatment in animal models of acute lung injury. Mice lacking MG53 show increased susceptibility to ischemia-reperfusion and over-ventilation induced injury to the lung when compared with wild type mice. Extracellular application of recombinant human MG53 (rhMG53) protein protects cultured lung epithelial cells against anoxia/reoxygenation-induced injuries. Intravenous delivery or inhalation of rhMG53 reduces symptoms in rodent models of acute lung injury and emphysema. Repetitive administration of rhMG53 improves pulmonary structure associated with chronic lung injury in mice. Our data indicate a physiological function for MG53 in the lung and suggest that targeting membrane repair may be an effective means for treatment or prevention of lung diseases.

1 The purpose of this study was to investigate the antitussive activity and sites of action of the NK 1 and NK 2 tachykinin receptor antagonists, 994, SR 48968, and the racemate of SR 48968, SR 48212A in the cat and guinea-pig. 2 Guinea-pigs were dosed subcutaneously (s.c.) with CP-99,994, SR 48212A or SR 48968 one hour before exposure to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted. 3 Intracerebroventricular (i.c.v.) cannulae were placed in the lateral cerebral ventricles of anaesthetized guinea-pigs. Approximately one week later, the animals were dosed with 994 or SR 48212A (i.c.v.) and exposed to aerosols of capsaicin (0.3 mM) to elicit coughing. 4 Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was monitored from electromyograms of respiratory muscle activity. Cannulae were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of CP-99,994, SR 48212A or SR 48968. Dose-response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED 50 to i.a. ED 50 , known as the e ective dose ratio (EDR). The EDR will be 20 or greater for a centrally active drug and less than 20 for a peripherally active drug. 5 In the guinea-pig, CP-99,994 (0.1 ± 30 mg kg 71 , s.c.), SR 48212A (1.0 ± 30 mg kg 71 , s.c.), and SR 48968 (0.3 ± 3.0 mg kg 71 , s.c.) inhibited capsaicin-induced cough in a dose-dependent manner. Capsaicininduced cough was also inhibited by i.c.v. administration of CP-99,994 (10 and 100 mg) or SR 48212A (100 mg). 6 In the cat, both CP-99,994 (0.0001 ± 0.3 mg kg 71 , i.a., n=5; 0.003 ± 3.0 mg kg 71 , i.v., n=5) and SR 48212A (0.003 ± 1.0 mg kg 71 , i.a., n=5; 0.01 ± 3.0 mg kg 71 , i.v., n=5) inhibited mechanically induced cough by either the i.v. or i.a. routes in a dose-dependent manner. SR 48968 (0.001 ± 0.3 mg kg 71 , i.a., n=5; 0.03 ± 1.0 mg kg 71 , i.v., n=5) inhibited cough when administered by the i.a. route in a dosedependent manner, but had no e ect by the i.v. route up to a dose of 1.0 mg kg 71 . Intravenous antitussive potencies (ED 50 , 95% con®dence interval (CI)) of these compounds were: CP-99,994 (0.082 mg kg 71 , 95% CI 0.047 ± 0.126), SR 48212A (2.3 mg kg 71 , 95% CI 0.5 ± 20), and SR 48968 (41.0 mg kg 71 , 95% CI not determined). The intra-arterial potencies of these compounds were: CP-99,994 (1.0 mg kg 71 , 95% CI 0.4 ± 1.8), SR 48212A (25 mg kg 71 , 95% CI 13 ± 52), and SR 48968 (8.0 mg kg 71 , 95% CI 1 ± 32). The derived EDRs for each compound were: 994, 82; SR 48212A, 92; and SR 48968, 4125. 7 We concluded that CP-99,994 and SR 48968 inhibit cough in the guinea-pig and cat by a central site of action. In the cat, the antitussive action of these compounds appears to be solely by a central site.

Endogenous neuronal lipid mediator anandamide, which can be synthesized in the lung, is a ligand of both cannabinoid (CB) and vanilloid receptors (VR). The tussigenic effect of anandamide has not been studied. The current study was designed to test the direct tussigenic effect of anandamide in conscious guinea‐pigs, and its effect on VR1 receptor function in isolated primary guinea‐pig nodose ganglia neurons. Anandamide (0.3–3 mg·ml−1), when given by aerosol, induced cough in conscious guinea‐pigs in a concentration dependent manner. When guinea‐pigs were pretreated with capsazepine, a VR1 antagonist, the anandamide‐induced cough was significantly inhibited. Pretreatment with CB1 (SR 141716A) and CB2 (SR 144528) antagonists had no effect on anandamide‐induced cough. These results indicate that anandamide‐induced cough is mediated through the activation of VR1 receptors. Anandamide (10–100 μM) increased intracellular Ca2+ concentration estimated by Fluo‐4 fluorescence change in isolated guinea‐pig nodose ganglia cells. The anandamide‐induced Ca2+ response was inhibited by two different VR1 antagonists: capsazepine (1 μM) and iodo‐resiniferatoxin (I‐RTX, 0.1 μM), indicating that anandamide‐induced Ca2+ response was through VR1 channel activation. In contrast, the CB1 (SR 141716A, 1 μM) and CB2 (SR 144528, 0.1 μM) receptor antagonists had no effect on Ca2+ response to anandamide. In conclusion, these results provide evidence that anandamide activates native vanilloid receptors in isolated guinea‐pig nodose ganglia cells and induces cough through activation of VR1 receptors. British Journal of Pharmacology (2002) 137, 831–836. doi:

We studied the pharmacological actions of combined histamine H1/H3 receptor blockade on the increase in nasal airway resistance (NAR) and decrease in nasal cavity volume produced by nasal exposure to compound 48/80, a mast cell degranulator. In the anesthetized cat compound 48/80 (1%) produced a maximum increase in NAR of 9.1 +/- 0.7 cmH20.L/minute. The increase in NAR in animals pretreated with a combination of the H1 antagonist, chlorpheniramine (CTM; 0.8 mg/kg i.v.) and increasing doses of the H3 antagonist, thioperamide (THIO; 1.0, 3.0, and 10.0 mg/kg i.v.) were 6.1 +/- 2.1, 4.2 +/- 1.0 and 2.2 +/- 0.7 cmH20.L/minute, respectively. A second H3 antagonist, clobenpropit (CLOB; 0.03, 0.3, and 1.0 mg/kg i.v.) combined with CTM (0.8 mg/kg i.v.) also inhibited the nasal effects of compound 48/80. When the nonsedating H1 antihistamine, loratadine (3.0 mg/kg i.v.), was substituted for CTM, it also reduced nasal congestion when given in combination with THIO (10 mg/kg i.v.). In contrast, treatment with CTM (1.0 mg/kg i.v.) and the H2 antagonist, ranitidine (RAN; 1.0 mg/kg i.v.) were without activity. Loratadine, CTM, CLOB, RAN, or THIO administered alone were inactive. The alpha-adrenergic agonist, phenylpropanolamine (PPA; 1.0 mg/kg i.v.) demonstrated decongestant effects, but in contrast to H1/H3 blockade, PPA produced a significant hypertensive effect. Using acoustic rhinometry (AcR) we found that combined i.v. CTM (1.0 mg/kg) and THIO (10 mg/kg) and combined oral CTM (10 mg/kg) and THIO (30 mg/kg) blocked the decrease in nasal cavity volume produced by intranasal compound 48/80 (1%, 50 microL). We conclude that combined H1/H3 histamine receptor blockade enhances the efficacy of an H1 antagonist by conferring decongestant activity to the H1 antihistamine. We propose that the decongestant activity of combined H1/H3 blockade may provide a novel approach for the treatment of allergic nasal congestion without the hypertensive liability of current therapies.

No abstract

We studied the central and peripheral antitussive eect of ORL 1 receptor activation with nociceptin/ orphanin FQ in conscious guinea-pigs. In guinea-pig cough studies, nociceptin/orphanin FQ (10, 30, and 90 mg) given directly into the CNS by an intracerebroventricular (i. ) also inhibited cough approximately by 25 and 42%, respectively. These ®ndings indicate that selective ORL 1 agonists display the potential to inhibit cough by both a central and peripheral mechanism, and potentially represent a novel therapeutic approach for the treatment of cough.

No abstract

Currently, opiates are widely used as antitussives but have substantial side effects. Recently, it has been proposed that NOP1 receptor agonists may be useful as a novel approach to cough suppression. Therefore, we compared the effect of NOP1 receptor agonist SCH486757 with matched placebo and codeine in a multicentre, double-blind, parallel-group study in patients with subacute cough. The primary outcome was change in cough severity scores, with the key secondary outcome change in objective daytime cough counts. We studied 91 subjects with subacute cough [59 (65%) female, median age = 41(range = 18-64) years, and median cough duration = 33 (range = 16-99) days]. Subjects were randomised to receive either SCH486757 100 mg, codeine 30 mg, or matched placebo twice daily for 5 days. Cough severity was scored throughout using a diary card and objective cough frequency recorded for 8 h at baseline and on the first and last treatment days. There were no significant differences in changes in average cough severity scores from baseline to treatment between SCH486757 and placebo [mean change = -0.57 (-30.1%) vs. mean change = -0.49 (-19.7%); P = 0.56] or between codeine and placebo [mean change = -0.72 (-33.2%); P = 0.07 compared to placebo). Changes in objective cough counts also showed no differences between the three treatment groups. There were some hints of possible limited antitussive efficacy with SCH486757. Unfortunately, the maximum clinical dose is limited by its tendency to produce somnolence. If the therapeutic ratio of NOP1 agonists could be improved, these drugs may still prove to contain effective antitussives.