title: The orl rat is more responsive to methacholine challenge than wild type.
abstract: BACKGROUND
  This study presents an animal model of native airway hyperresponsiveness (AHR). AHR is a fundamental aspect of asthma and reflects an abnormal response characterized by airway narrowing following exposure to a wide variety of non-immunological stimuli. Undescended testis (UDT) is one of the most common male congenital anomalies. The orl rat is a Long Evans substrain with inherited UDT. Since boys born with congenital UDT are more likely to manifest asthma symptoms, the main aim of this study was to investigate the alternative hypothesis that orl rats have greater AHR to a methacholine aerosol challenge than wild type rats.
  
  
  METHODS
  Long Evans wild type (n = 9) and orl (n = 13) rats were anesthetized, tracheostomized, and mechanically ventilated at 4 weeks of age. Escalating concentrations of inhaled methacholine were delivered. The methacholine potency and efficacy in the strains were measured. Respiratory resistance was the primary endpoint. After the final methacholine aerosol challenge, the short-acting β2-adrenoceptor agonist albuterol was administered as an aerosol and lung/diaphragm tissues were assayed for interleukin (IL)-4, IL-6, and tumor necrosis factor (TNF)-α. Histological and histomorphometrical analyses were performed.
  
  
  RESULTS
  The methacholine concentration-response curve in the orl group indicated increased sensitivity, hyperreactivity, and exaggerated maximal response in comparison with the wild type group, indicating that orl rats had abnormally greater AHR responses to methacholine. Histological findings in orl rats showed the presence of eosinophils, unlike wild type rats. β2-Adrenoceptor agonist intervention resulted in up-regulation of IL-4 diaphragmatic levels and down-regulation of IL-4 and IL-6 in the lungs of orl rats.
  
  
  CONCLUSIONS
  orl rats had greater AHR than wild type rats during methacholine challenge, with higher IL-4 levels in diaphragmatic tissue homogenates. Positive immunostaining for IL-4 was detected in lung and diaphragmatic tissue in both strains. This model offers advantages over other pre-clinical murine models for studying potential mechanistic links between cryptorchidism and asthma. This animal model may be useful for further testing of compounds/therapeutics options for treating AHR.
authors.affiliation: Alfred I. duPont Hospital for Children, Nemours Lung Center, Wilmington, DE 19803, United States; Alfred I. duPont Hospital for Children, Nemours Biomedical Research, Wilmington, DE 19803, United States; Thomas Jefferson University, Division of Clinical Pharmacology, Dept. of Pharmacology and Experimental Therapeutics, Philadelphia, PA 19107, United States. Electronic address: elena.radtke@icloud.com.
authors.forename: Elena
authors.initials: E
authors.lastname: Rodriguez
authors.affiliation: Alfred I. duPont Hospital for Children, Nemours Biomedical Research, Wilmington, DE 19803, United States; Nemours Alfred I. duPont Hospital for Children, Division of Urology, Wilmington, DE 19803, United States.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Barthold
authors.affiliation: Nemours Alfred I. duPont Hospital for Children, Department of Pathology, Wilmington, DE 19803, United States.
authors.forename: Portia A
authors.initials: PA
authors.lastname: Kreiger
authors.affiliation: Alfred I. duPont Hospital for Children, Nemours Lung Center, Wilmington, DE 19803, United States; Alfred I. duPont Hospital for Children, Nemours Biomedical Research, Wilmington, DE 19803, United States.
authors.forename: Milena Hirata
authors.initials: MH
authors.lastname: Armani
authors.affiliation: Alfred I. duPont Hospital for Children, Nemours Lung Center, Wilmington, DE 19803, United States.
authors.forename: Jordan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Alfred I. duPont Hospital for Children, Nemours Lung Center, Wilmington, DE 19803, United States; Alfred I. duPont Hospital for Children, Nemours Biomedical Research, Wilmington, DE 19803, United States.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Michelini
authors.affiliation: Temple University School of Medicine, Department of Physiology, Philadelphia, PA 19140, United States; Temple University School of Medicine, Department of Pediatrics, Philadelphia, PA 19140, United States.
authors.forename: Marla R
authors.initials: MR
authors.lastname: Wolfson
authors.affiliation: Alfred I. duPont Hospital for Children, Histotechnology Core Laboratory, Wilmington, DE 19803, United States.
authors.forename: Roberta
authors.initials: R
authors.lastname: Boyce
authors.affiliation: Alfred I. duPont Hospital for Children, Histotechnology Core Laboratory, Wilmington, DE 19803, United States.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Barone
authors.affiliation: Alfred I. duPont Hospital for Children, Nemours Lung Center, Wilmington, DE 19803, United States; Alfred I. duPont Hospital for Children, Nemours Biomedical Research, Wilmington, DE 19803, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Thomas Jefferson University, Division of Clinical Pharmacology, Dept. of Pharmacology and Experimental Therapeutics, Philadelphia, PA 19107, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
authors.affiliation: Alfred I. duPont Hospital for Children, Nemours Lung Center, Wilmington, DE 19803, United States; Temple University School of Medicine, Department of Physiology, Philadelphia, PA 19140, United States; Temple University School of Medicine, Department of Pediatrics, Philadelphia, PA 19140, United States.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Shaffer
mesh_terms: D000280:Administration, Inhalation; D000420:Albuterol / Q000627:therapeutic use; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D001249:Asthma / Q000139:chemically induced* / Q000503:physiopathology; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003456:Cryptorchidism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015847:Interleukin-4 / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020318:Rats, Long-Evans; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D018927:Anti-Asthmatic Agents; D016085:Bronchoconstrictor Agents; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D015847:Interleukin-4; D000420:Albuterol
keywords: Airway hyperresponsiveness; Airway pharmacology; Albuterol sulfate (PubChem CID: 39859); Asthma; Bronchoconstriction; Hyperreactivity; Lung inflammation; Methacholine chloride (PubChem CID: 6114)