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.
Spleen tyrosine kinase (SYK) is a key activator of signaling pathways downstream of multiple surface receptors implicated in asthma. SYK function has been extensively studied in mast cells downstream of the high-affinity IgE receptor, FcεR1. Preclinical studies have demonstrated a role for SYK in models of allergic inflammation, but a role in airway constriction has not been demonstrated. Here, we have used a potent and selective pharmacological inhibitor of SYK to determine the role of SYK in allergen-mediated inflammation and airway constriction in preclinical models. Attenuation of allergic airway responses was evaluated in a rat passive anaphylaxis model and rat and sheep inhaled allergen challenge models, as well as an ex vivo model of allergen-mediated airway constriction in rats and cynomolgus monkeys. Pharmacological inhibition of SYK dose-dependently blocked IgE-mediated tracheal plasma extravasation in rats. In a rat ovalbumin-sensitized airway challenge model, oral dosing with an SYK inhibitor led to a dose-dependent reduction in lung inflammatory cells. Ex vivo analysis of allergen-induced airway constriction in ovalbumin-sensitized brown Norway rats showed a complete attenuation with treatment of a SYK inhibitor, as well as a complete block of allergen-induced serotonin release. Similarly, allergen-mediated airway constriction was attenuated in ex vivo studies from nonhuman primate lungs. Intravenous administration of an SYK inhibitor attenuated both early- and late-phase allergen-induced increases in airway resistance in an Ascaris-sensitive sheep allergen challenge model. These data support a key role for SYK signaling in mediating allergic airway responses.
Background: Histamine and cysteinyl leukotrienes are pivotal mast cell mediators which contribute considerably and likely complementary to the symptoms of allergic rhinitis. Currently, we sought to explore the direct actions of histamine and leukotriene D4 (LTD4), a cysteinyl leukotriene, on porcine nasal arteries and veins. We also studied combined blocks of histamine and cysteinyl leukotrienes using loratadine and montelukast in an in vivo model of allergy-mediated nasal inflammation. Methods: For the evaluation of the action of histamine and LTD4 on arteries and veins, porcine nasal mucosa was isolated and cut into slices (100–300 µm thick). Real-time images of the nasal arteries and veins were recorded and vessel activities estimated by changes in cross-sectional area before and after the tested drugs. For the in vivo studies, the effect of loratadine and montelukast given alone and in combination was examined on upper airway inflammation in ovalbumin-sensitized and -challenged Brown Norway rats. Results: Both histamine (0.001–10 µmol/l) and LTD4 (0.001–10 µmol/l) produced a concentration-dependent increase in the lumen area of nasal mucosa arteries and veins. Histamine (0.01 µmol/l) alone produced a 24 and 12% increase in cross-sectional areas of arteries and veins, respectively. LTD4 (0.001 µmol/l) alone increased artery and vein dilation by about 17 and 9%, respectively. Combination treatment with histamine (0.01 µmol/l) and LTD4 (0.001 µmol/l) increased vessel dilation by 65% (arteries) and 26% (veins). In our in vivo Brown Norway rat studies, oral loratadine (0.01–10 mg/kg) and montelukast (0.01–10 mg/kg) significantly reduced antigen-induced total nasal inflammatory cell infiltration in a dose-dependent manner. The antiinflammatory dose-response curve of loratadine was shifted to the left when studied in combination with montelukast (0.01 mg/kg). Similarly, the dose-response characteristics of montelukast (0.01–10 mg/kg) was shifted in the presence of loratadine (0.01 mg/kg). Conclusion: Our studies support the position that histamine and cysteinyl leukotrienes may act collaboratively to elicit allergic nasal pathologies such as upper airway inflammation and nasal vessel dilation (which may translate into increased nasal mucosal engorgement). Furthermore, the current results are supportive of the hypothesis that combined treatment of allergic rhinitis with an H1 receptor antagonist and a CysLT1 receptor antagonist may have greater benefit than sole treatment with these agents alone.
Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective a2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/ pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of a2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 ml). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1-3.0 mg/kg), compound B (0.3-5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike dpseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC 80 ) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that a2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.
Methods in rodents to inform on oral controlled release (CR) formulations in the drug discovery process are limited. To address this problem, here we describe slow gastric infusion in rats as an approach that may allow for more informed decision‐making regarding investment in formulation based CR. To evaluate this approach, we used a novel orally bioavailable NO donor to determine whether slow compound delivery directly to the stomach would extend the duration of action of blood pressure (BP) lowering for a compound with a short T1/2 and minimize abrupt decreases in BP and increases in heart rate (HR) observed for vasorelaxants with early Tmax and high Cmax. BP and HR are particularly advantageous pharmacodynamics (PD) readouts because continuous measurements provide rich data sets for PK/PD comparisons. To inform on study design, an aqueous vehicle for compound solubilization was identified (30% HPBCD) and used to determine dose and predict plasma level concentrations following slow gastric infusion. For PD studies, Sprague‐Dawley rats were instrumented with telemetry and gastric tubes. After surgical recovery, rats were treated with L‐NAME to induce hypertension followed by a 30 mg/kg dose of NO donor compound, administered as a bolus and a slow 24‐hr infusion via gastric tube. Compared to a bolus dose, slow gastric infusion extended the duration of BP lowering, minimized the abrupt fall in blood pressure, and inhibited the increase in heart rate. In conclusion, our data support slow gastric infusion as a means to test PK/PD hypotheses which may inform on effectiveness of CR formulations.
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