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Brian Schofield

Publications and source records attributed to Brian Schofield.

13 recordsLinked to original sources
PubMed2007

Variation in senescent-dependent lung changes in inbred mouse strains.

Previous studies from our laboratories showed lung development differences between inbred strains of mice. In the present study, the C57BL/6J (B6) and DBA/2J (D2) strains were examined for senescent-dependent differences with respect to the lung structure and function. Specifically, we hypothesize that senescent changes in lung vary between strains due to identifiable gene expression differences. Quasi-static pressure-volume curves and respiratory impedance measurements were performed on 2- and 20-mo-old B6 and D2 mice. Lung volume at 30 cm H(2)O (V(30)) pressure was significantly (P < 0.01) increased with age in both strains, but the increase was proportionally greater in D2 (68%) than in B6 (40%) mice. In addition, decreased elastic recoil pressure at 50% of V(30) and a reduction in airway resistance as a function of positive end-expiratory pressure were observed in 20-mo-old D2 mice but not in B6 mice. Morphometric analysis of lung parenchyma showed significant decreases in elastic fiber content with age in both strains, but the collagen content was significantly (P < 0.01) increased with age in D2 but not B6 mice at 20 mo. Furthermore, using quantitative RT-PCR methods, gene expression differences between strains suggested that D2 mice significantly (P < 0.05) downregulated the expressions of elastin (Eln) and procollagen I, III, and VI (Col1a1, Col3a1, and Col6a3) in lung tissue at 20 mo of age. These age-dependent changes were accompanied by an increased gene expression in matrix metalloproteinase 9 (Mmp9) in D2 and an increase in tissue inhibitor of matrix metalloproteinase (Timp1 and Timp4) in B6 mice. In conclusion, the results from the present study demonstrate that lung mechanics of both strains show significant age-dependent changes. However, changes in D2 mice are accelerated relative to B6 mice. Moreover, gene expression differences appear to be involved in the strain-specific changes of lung mechanic properties.

Aging↗
PubMed2006

C5 modulates airway hyperreactivity and pulmonary eosinophilia during enhanced respiratory syncytial virus disease by decreasing C3a receptor expression.

Enhanced respiratory syncytial virus disease, a serious pulmonary disorder that affected recipients of an inactivated vaccine against respiratory syncytial virus in the 1960s, has delayed the development of vaccines against the virus. The enhanced disease was characterized by immune complex-mediated airway hyperreactivity and a severe pneumonia associated with pulmonary eosinophilia. In this paper, we show that complement factors contribute to enhanced-disease phenotypes. Mice with a targeted disruption of complement component C5 affected by the enhanced disease displayed enhanced airway reactivity, lung eosinophilia, and mucus production compared to wild-type mice and C5-deficient mice reconstituted with C5. C3aR expression in bronchial epithelial and smooth muscle cells in the lungs of C5-deficient mice was enhanced compared to that in wild-type and reconstituted rodents. Treatment of C5-deficient mice with a C3aR antagonist significantly attenuated airway reactivity, eosinophilia, and mucus production. These results indicate that C5 plays a crucial role in modulating the enhanced-disease phenotype, by affecting expression of C3aR in the lungs. These findings reveal a novel autoregulatory mechanism for the complement cascade that affects the innate and adaptive immune responses.

Animals↗
PubMed2006

Age-dependent changes of airway and lung parenchyma in C57BL/6J mice.

In the current study, we hypothesize that senescent-dependent changes between airway and lung parenchymal tissues of C57BL/6J (B6) mice are not synchronized with respect to altered lung mechanics. Furthermore, aging modifications in elastin fiber and collagen content of the airways and lung parenchyma are remodeling events that differ with time. To test these hypotheses, we performed quasi-static pressure-volume (PV) curves and impedance measurements of the respiratory system in 2-, 20-, and 26-mo-old B6 mice. From the PV curves, the lung volume at 30 cmH(2)O pressure (V(30)) and respiratory system compliance (Crs) were significantly (P < 0.01) increased between 2 and 20 mo of age, representing about 80-84% of the total increase that occurred between 2 and 26 mo of age. Senescent-dependent changes in tissue damping and tissue elastance were analogous to changes in V(30) and Crs; that is, a majority of the parenchymal alterations in the lung mechanics occurred between 2 and 20 mo of age. In contrast, significant decreases in airway resistance (R) occurred between 20 and 26 mo of age; that is, the decrease in R between 2 and 20 mo of age represented only 29% (P > 0.05) of total decrease occurring through 26 mo. Morphometric analysis of the elastic fiber content in lung parenchyma was significantly (P < 0.01) decreased between 2 and 20 mo of age. To the contrary, increased collagen content was significantly delayed until 26 mo of age (P < 0.01, 2 vs. 26 mo). In conclusion, our data demonstrate that senescent-dependent changes in airway and lung tissue mechanics are not synchronized in B6 mice. Moreover, the reduction in elastic fiber content with age is an early lung remodeling event, and the increased collagen content in the lung parenchyma occurs later in senescence.

Aging↗
PubMed2005

Pulmonary ischemia induces lung remodeling and angiogenesis.

Cellular remodeling during angiogenesis in the lung is poorly described. Furthermore, it is the systemic vasculature of the lung and surrounding the lung that is proangiogenic when the pulmonary circulation becomes impaired. In a mouse model of chronic pulmonary thromboembolism, after left pulmonary artery ligation (LPAL), the intercostal vasculature, in proximity to the ischemic lung, proliferates and invades the lung (12). In the present study, we performed a detailed investigation of the kinetics of remodeling using histological sections of the left lung of C57Bl/6J mice after LPAL (4 h to 20 days) or after sham surgery. New vessels were seen within the thickened visceral pleura 4 days after LPAL predominantly in the upper portion of the left lung. Connections between new vessels within the pleura and pulmonary capillaries were clearly discerned by 7 days after LPAL. The visceral pleura and the lung parenchyma showed intense tissue remodeling, as evidenced by markedly elevated levels of both proliferating cell nuclear antigen and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive cells. Rapidly dividing cells were predominantly macrophages and type II pneumocytes. The increased apoptotic activity was further quantified by caspase-3 activity, which showed a sixfold increase relative to naive lungs, by 24 h after LPAL. Because sham surgeries had little effect on measured parameters, we conclude that both thoracic wound healing and pulmonary ischemia are required for systemic neovascularization.

Animals↗
PubMed2005

Chronic exposure to TNF-alpha increases airway mucus gene expression in vivo.

BACKGROUND: Hypersecretion of mucus plays an important role in the pathogenesis and severity of asthma. The primary proteins in mucus are mucin glycoproteins; MUC-5AC is the primary airway mucin gene. The calcium chloride-activated channel gene hCLCA1 (gob-5 in the mouse) has been suggested to increase MUC-5AC gene expression, and both are increased in asthmatic patients and murine models. TNF-alpha increases the expression of these genes in vitro but has not been investigated in vivo. OBJECTIVE: We sought to determine whether TNF-alpha increases gene expression of gob-5 and MUC-5AC and induces mucus cell metaplasia in vivo. METHODS: Naive BALB/c mice received 50 ng of recombinant murine TNF-alpha (rmTNF-alpha) intratracheally daily for 1, 2, or 3 weeks; another group received the same dose of intratracheal rmTNF-alpha daily for 3 weeks and then alternate-day treatment for 3 additional weeks (total of 6 weeks). AKR mice received 50 ng of rmTNF-alpha intratracheally for 3 or 6 weeks daily. Naive nontreated mice were used as control animals. Airway gene products for gob-5 and MUC-5AC were determined by means of real-time PCR. Lung tissue sections were stained with periodic acid-Schiff/Alcian blue to assess mucus cell metaplasia. RESULTS: rmTNF-alpha significantly increased gene expression of airway gob-5 and MUC-5AC after 2 weeks in the BALB/c mice. There was noticeable mucus staining in all mice treated for at least 3 weeks with TNF-alpha and in 80% of the mice receiving 2 weeks of treatment. After 3 weeks of treatment, the AKR mice also showed increased gob-5 expression. CONCLUSIONS: This study demonstrates for the first time that TNF-alpha alone in vivo is sufficient to increase airway mucus gene expression in 2 murine strains.

Animals↗
PubMed2004

The potential use of Chinese herbal medicines in treating allergic asthma.

OBJECTIVE: To discuss the potential use of the Chinese herbal formula MSSM-002 in treating asthma based on its effects on a murine model of allergic asthma, immunoregulatory actions on T(H)2 cells in vitro, and the means of standardization for herbal formula quality control. DATA SOURCES: Information presented at the 2002 American College of Allergy, Asthma and Immunology (ACAAI) Annual Scientific Meeting International Symposium on Complementary Alternative Medicine in San Antonio, TX. STUDY SELECTION: All presentations from the ACAAI meeting that discussed MSSM-002 were considered for this review. RESULTS: The Chinese herbal formula MSSM-002 suppressed airway hyperreactivity and eosinophilic inflammation in a murine model of allergic asthma. These effects were comparable to dexamethasone but were not accompanied by the suppression of T(H)1 responses seen with dexamethasone. In vitro studies demonstrated that MSSM-002 significantly decreased antigen-induced T(H)2 cytokine secretion by murine T(H)2 polarized splenocytes and human mucosal T(H)2 cell lines, which in contrast to dexamethasone did not cause apoptosis and was not cytotoxic but was associated with decreased GATA-3 expression. Chromatographic fingerprints of MSSM-002 and evaluation of in vivo actions showed that the quality of several batches of MSSM-002 was consistent. CONCLUSION: MSSM-002 has a therapeutic effect on allergic asthma and immunoregulatory actions on established T(H)2 cells and may prove to be of potential clinical benefit to asthma patients.

Animals↗
PubMed2003

Persistent protective effect of heat-killed Escherichia coli producing "engineered," recombinant peanut proteins in a murine model of peanut allergy.

BACKGROUND: Peanut allergy (PNA) is a life-threatening food allergy for which there is no definitive treatment. OBJECTIVE: We investigated the long-term immunomodulatory effect of heat-killed Escherichia coli producing engineered (mutated) Ara h1, 2, and 3 (HKE-MP123) administered rectally (pr) in a murine model of PNA. METHODS: Peanut-allergic C3H/HeJ mice received 0.9 (low dose), 9 (medium dose), or 90 (high dose) microg HKE-MP123 pr, HKE-containing vector (HKE-V) alone, or vehicle alone (sham) weekly for 3 weeks. Mice were challenged 2 weeks later. A second and third challenge were performed at 4-week intervals. RESULTS: After the first challenge, all 3 HKE-MP123 and HKE-V-treated groups exhibited reduced symptom scores (P <.01,.01,.05,.05, respectively) compared with the sham-treated group. Interestingly, only the medium- and high-dose HKE-MP123-treated mice remained protected for up to 10 weeks after treatment accompanied by a significant reduction of plasma histamine levels compared with sham-treated mice (P <.05 and.01, respectively). IgE levels were significantly lower in all HKE-MP123-treated groups (P <.001), being most reduced in the high-dose HKE-MP123-treated group at the time of each challenge. IL-4, IL-13, IL-5, and IL-10 production by splenocytes of high-dose HKE-MP123-treated mice were significantly decreased (P <.01;.001,.001, and.001, respectively), and IFN-gamma and TGF-beta production were significantly increased (P <.001 and.01, respectively) compared with sham-treated mice at the time of the last challenge. CONCLUSIONS: Treatment with pr HKE-MP123 can induce long-term "downregulation" of peanut hypersensitivity, which might be secondary to decreased antigen-specific T(H)2 and increased T(H)1 and T regulatory cytokine production.

2S Albumins, Plant↗
PubMed2003

Structural and functional differences of the carotid body between DBA/2J and A/J strains of mice.

In a previous study, DBA/2J and A/J inbred mice showed extremely different hypoxic ventilatory responses, suggesting variations in their carotid bodies. We have assessed the morphological and functional differences of the carotid bodies in these mice. Histological examination revealed a clearly delineated carotid body only in the DBA/2J mice. Many typical glomus cells and glomeruli appeared in the DBA/2J but not in the A/J mice. The size of the carotid body in the DBA/2J and A/J mice was 6.3 +/- 0.5 x 10(6) and 1.5 +/- 0.3 x 10(6) micro m(3), respectively. The area immunostained for tyrosine hydroxylase, an estimation of the glomus cell quantity, was four times larger in the DBA/2J mice than in the A/J mice. The individual data points in the DBA/2J mice segregated from those in the A/J mice. ACh increased intracellular Ca(2+) in most clusters (81%) of cultured carotid body cells from the DBA/2J mice, but only in 18% of clusters in the A/J mice. These data suggest that genetic determinants account for the strain differences in the structure and function of the carotid body.

Acetylcholine↗
PubMed2003

Repeated peripheral airway hyperpnea causes inflammation and remodeling in dogs.

INTRODUCTION/PURPOSE: Elite winter athletes have an increased incidence of asthma, the cause of which is unknown. Strenuous exercise, particularly while breathing cold air, results in airway cooling and desiccation. We used a canine model of hyperpnea with cold, dry air to test the hypothesis that repeated cooling and desiccation of peripheral airways can cause asthma-like pathology. METHODS: Canine sublobar airways were challenged with room temperature, dry air insufflated though a bronchoscope to simulate the mucosal cooling and desiccation that occurs in human peripheral airways during strenuous cold weather exercise. Airways were challenged once daily on four consecutive days, and control and challenged airways were harvested 24 h after the last challenge for histological analyses. RESULTS: Repeated challenge caused airway obstruction and remodeling that persisted for at least 24 h. The percentage of mucosal squamous epithelium increased with a corresponding decrease in ciliated epithelium. Challenged airways had thicker lamina propria that contained greater concentrations of eosinophils, neutrophils, and mast cells when compared with control airways. The severity of airway obstruction was correlated with mucosal condition, airway thickness, and eosinophil infiltration. With the exception of mast cell infiltration, all changes were reversed within 1 wk of cessation of challenges. CONCLUSIONS: We conclude that repeated cooling and desiccation of peripheral airways can cause airway remodeling similar to that seen in asthma. These findings, in concert with other reports using this model, support the hypothesis that asthma-like symptoms found in winter athletes may be the result of repeated hyperpnea with cold air.

Air↗
PubMed2002

Complement factor 3 mediates particulate matter-induced airway hyperresponsiveness.

Epidemiologic studies have suggested that exposure to airborne particulate matter (PM) can exacerbate allergic airway responses; however, the mechanism(s) are not well understood. We and others have recently shown that development of airway hyperresponsiveness (AHR) may be a complement-mediated process. In the present study, we examined the role of complement factor 3 (C3) in the development of PM-induced AHR and airway inflammation by comparing responses between C3-deficient (C3(-/-)) and wild-type mice. Mice were exposed to 0.5 mg of ambient particulate collected in urban Baltimore. Forty-eight hours later, airway responsiveness to intravenous acetylcholine was assessed and bronchoalveolar lavage was conducted. PM exposure of wild-type mice resulted in significant increases in AHR, whereas it did not significantly increase airway reactivity in C3(-/-) mice. Interestingly, PM induced similar inflammatory responses in both wild-type and C3(-/-) mice. Immunohistochemical staining demonstrated marked C3 deposition in the airway epithelium and connective tissue of wild-type mice after PM exposure. These results suggest that exposure to PM may induce AHR through activation of complement factor 3 in the airways.

Air Pollution↗