Reduced peribronchial fibrosis in allergen-challenged MMP-9-deficient mice

2006 ◽  
Vol 291 (2) ◽  
pp. L265-L271 ◽  
Author(s):  
Dae Hyun Lim ◽  
Jae Youn Cho ◽  
Marina Miller ◽  
Kirsti McElwain ◽  
Shauna McElwain ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Remodeling ◽  
Muscle Thickness ◽  
Muscle Layer ◽  
Airway Responsiveness ◽  
Wild Type ◽  
Extracellular Proteases ◽  
Significant Difference ◽  
Deficient Mice ◽  
Modest Reduction

Matrix metalloproteinases (MMPs) are a family of extracellular proteases that are responsible for the degradation of the extracellular matrix during tissue remodeling. We have used a mouse model of allergen-induced airway remodeling to determine whether MMP-9 plays a role in airway remodeling. MMP-9-deficient and wild-type (WT) mice were repetitively challenged intranasally with ovalbumin (OVA) antigen to develop features of airway remodeling including peribronchial fibrosis and increased thickness of the peribronchial smooth muscle layer. OVA-challenged MMP-9-deficient mice had less peribronchial fibrosis and total lung collagen compared with OVA-challenged WT mice. There was no reduction in mucus expression, smooth muscle thickness, or airway responsiveness in OVA-challenged MMP-9-deficient compared with OVA-challenged WT mice. OVA-challenged MMP-9-deficient mice had reduced levels of bronchoalveolar lavage (BAL) regulated on activation, normal T cell expressed, and secreted (RANTES), as well as reduced numbers of BAL and peribronchial eosinophils compared with OVA-challenged WT mice. There were no significant difference in levels of BAL eotaxin, thymus- and activation-regulated chemokine (TARC), or macrophage-derived chemokine (MDC) in OVA-challenged WT compared with MMP-9-deficient mice. Overall, this study demonstrates that MMP-9 may play a role in mediating selected aspects of allergen-induced airway remodeling (i.e., modest reduction in levels of peribronchial fibrosis) but does not play a significant role in mucus expression, smooth muscle thickness, or airway responsiveness.

scholarly journals Immunocytochemical Analyses and Targeted Gene Disruption of GTPBP1

2000 ◽  
Vol 20 (17) ◽  
pp. 6195-6200 ◽  
Author(s):  
Satoru Senju ◽  
Ken-ichi Iyama ◽  
Hironori Kudo ◽  
Shinichi Aizawa ◽  
Yasuharu Nishimura
Keyword(s):  
Smooth Muscle ◽  
Gene Disruption ◽  
Amino Acid Level ◽  
Embryonic Stem ◽  
Mutant Mice ◽  
Wild Type ◽  
Targeted Gene Disruption ◽  
Mouse Tissues ◽  
Significant Difference ◽  
Deficient Mice

ABSTRACT We previously identified a gene encoding a putative GTPase, GTPBP1, which is structurally related to elongation factor 1α, a key component of protein biosynthesis machinery. The primary structure of GTPBP1 is highly conserved between human and mouse (97% identical at the amino acid level). Expression of this gene is enhanced by gamma interferon in a monocytic cell line, THP-1. Although counterparts of this molecule in Caenorhabditis elegans and Ascaris suum have also been identified, the function of this molecule remains to be clarified. In the present study, our immunohistochemical analyses on mouse tissues revealed that GTPBP1 is expressed in some neurons and smooth muscle cells of various organs as well as macrophages. Immunofluorescence analyses revealed that GTPBP1 is localized exclusively in cytoplasm and shows a diffuse granular network forming a gradient from the nucleus to the periphery of the cells in smooth muscle cell lines and macrophages. To investigate the physiological role ofGTPBP1, we used targeted gene disruption in embryonic stem cells to generate GTPBP1-deficient mice. The mutant mice were born at the expected Mendelian frequency, developed normally, and were fertile. No manifest anatomical or behavioral abnormality was observed in the mutant mice. Functions of macrophages, including chemotaxis, phagocytosis, and nitric oxide production, in mutant mice were equivalent to those seen in wild-type mice. No significant difference was observed in the immune response to protein antigen between mutant mice and wild-type mice, suggesting normal function of antigen-presenting cells of the mutant mice. The absence of an eminent phenotype in GTPBP1-deficient mice may be due to functional compensation by GTPBP2, a molecule we recently identified which is similar to GTPBP1 in structure and tissue distribution.

Interactions Between Leukotriene C4 and Interleukin 13 Signaling Pathways in a Mouse Model of Airway Disease

2006 ◽  
Vol 130 (4) ◽  
pp. 440-446
Author(s):  
Jaime Chavez ◽  
Hays W. J. Young ◽  
David B. Corry ◽  
Michael W. Lieberman
Keyword(s):  
Signaling Pathways ◽  
Airway Disease ◽  
Lavage Fluid ◽  
Airway Responsiveness ◽  
Leukotriene C4 ◽  
Wild Type ◽  
Transcript Levels ◽  
Interleukin 13 ◽  
Deficient Mice ◽  
Intranasal Instillation

Abstract Context.—During an asthmatic episode, leukotriene C4 (LTC4) and interleukin 13 (IL-13) are released into the airways and are thought to be central mediators of the asthmatic response. However, little is known about how these molecules interact or affect each other's signaling pathway. Objective.—To determine if the LTC4 and IL-13 signaling pathways interact with each other's pathways. Design.—We examined airway responsiveness, cysteinyl LTs (Cys-LTs), and Cys-LT and IL-13 receptor transcript levels in wild-type mice and in mice that were deficient in γ-glutamyl leukotrienase (an enzyme that converts LTC4 to LTD4), STAT6 (signal transducer and activator of transcription 6 [a critical molecule in IL-13 signaling]), and IL-4Rα (a subunit of the IL-13 receptor). Results.—Wild-type (C57BL/129SvEv) and γ-glutamyl leukotrienase–deficient mice showed increased airway responsiveness after intranasal instillation of IL-13; similar results were observed after intranasal instillation of IL-13 or LTC4 in a second wild-type strain (BALB/c). Interleukin 13 treatment reduced levels of Cys-LTs in bronchoalveolar lavage fluid. This change was unaccompanied by changes in other arachidonic acid metabolites or in RNA transcript levels of enzymes associated with Cys-LT synthesis. Interleukin 13 treatment also increased transcript levels of the Cys-LT 1 and Cys-LT 2 receptors, while LTC4 increased transcript levels of the α1 chain of the IL-13 receptor. Furthermore, IL-4Rα–deficient mice had increased airway responsiveness to LTC4 but not to IL-13, whereas STAT6-deficient mice failed to respond to either agonist. Conclusions.—These findings indicate that LTC4 and IL-13 are dependent on or signal through STAT6 to increase airway responsiveness and that both agonists regulate expression of each other's receptors.

Hyperoxia-induced airway hyperresponsiveness and remodeling in immature rats

1992 ◽  
Vol 262 (3) ◽  
pp. L263-L269 ◽  
Author(s):  
M. B. Hershenson ◽  
S. Aghili ◽  
N. Punjabi ◽  
C. Hernandez ◽  
D. W. Ray ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Muscle Layer ◽  
Airway Responsiveness ◽  
Wall Thickening ◽  
Small Airways ◽  
Smooth Muscle Layer ◽  
Hyperoxic Exposure ◽  
Immature Rats

We exposed 21-day-old rats to either normoxia or hyperoxia (greater than 95% O2) for 8 days and assessed in vivo airway responsiveness to aerosolized and intravenous methacholine (MCh) and airway architecture. Airway responsiveness was determined using a plethysmographic method. Hyperoxia increased airway cholinergic responsiveness, as reflected in a decreased mean ED200 (concentration of MCh required to increase respiratory system resistance by 100%) for both aerosolized MCh [air exposed, 5.94 +/- 2.50 vs. O2 exposed, 0.29 +/- 3.34 (SD) mg/ml, P = 0.0013, unpaired t test] and intravenous MCh (air, 1.40 x 10(-8) vs. O2, 2.45 x 10(-10) mol/kg, P = 0.0002). Airway morphometry was studied in a separate cohort of animals. After fixation by distension with Formalin at 25 cmH2O pressure, each airway cross section was photographed, and airway circumference, epithelial area, and smooth muscle layer area were determined by means of contour tracing using a digitizing pad and microcomputer. For the small airways (circumference less than 1,000 microns), hyperoxia increased both mean epithelial thickness (air, 4.88 +/- 0.53; O2, 8.64 +/- 0.90 microns) and mean smooth muscle layer thickness (air, 2.69 +/- 0.11; O2, 4.79 +/- 0.56 microns; P less than 0.0001 for each). O2 had similar effects on the larger (1,000-3,000 microns) central airways (P less than 0.0001 for both layers). We conclude that chronic hyperoxic exposure induces both airway hyperresponsiveness and airway wall thickening in immature rats.

scholarly journals Role of TRPP2 in mouse airway smooth muscle tension and respiration

2019 ◽  
Vol 317 (4) ◽  
pp. L466-L474 ◽  
Author(s):  
Dacheng Sang ◽  
Suwen Bai ◽  
Sheng Yin ◽  
Sen Jiang ◽  
Li Ye ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Transient Receptor Potential ◽  
Muscle Tension ◽  
Pulmonary Arteries ◽  
Conditional Knockout ◽  
Wild Type ◽  
High Potassium ◽  
Cross Sectional ◽  
Significant Difference

The transient receptor potential polycystin-2 (TRPP2) is encoded by the Pkd2 gene, and mutation of this gene can cause autosomal dominant polycystic kidney disease (ADPKD). Some patients with ADPKD experience extrarenal manifestations, including radiologic and clinical bronchiectasis. We hypothesized that TRPP2 may regulate airway smooth muscle (ASM) tension. Thus, we used smooth muscle- Pkd2 conditional knockout ( Pkd2SM-CKO) mice to investigate whether TRPP2 regulated ASM tension and whether TRPP2 deficiency contributed to bronchiectasis associated with ADPKD. Compared with wild-type mice, Pkd2SM-CKO mice breathed more shallowly and faster, and their cross-sectional area ratio of bronchi to accompanying pulmonary arteries was higher, suggesting that TRPP2 may regulate ASM tension and contribute to the occurrence of bronchiectasis in ADPKD. In a bioassay examining isolated tracheal ring tension, no significant difference was found for high-potassium-induced depolarization of the ASM between the two groups, indicating that TRPP2 does not regulate depolarization-induced ASM contraction. By contrast, carbachol-induced contraction of the ASM derived from Pkd2SM-CKO mice was significantly reduced compared with that in wild-type mice. In addition, relaxation of the carbachol-precontracted ASM by isoprenaline, a β-adrenergic receptor agonist that acts through the cAMP/adenylyl cyclase pathway, was also significantly attenuated in Pkd2SM-CKO mice compared with that in wild-type mice. Thus, TRPP2 deficiency suppressed both contraction and relaxation of the ASM. These results provide a potential target for regulating ASM tension and for developing therapeutic alternatives for some ADPKD complications of the respiratory system or for independent respiratory disease, especially bronchiectasis.

Differential response to myocardial reperfusion injury in eNOS-deficient mice

2002 ◽  
Vol 282 (6) ◽  
pp. H2422-H2426 ◽  
Author(s):  
Brent R. Sharp ◽  
Steven P. Jones ◽  
David M. Rimmer ◽  
David J. Lefer
Keyword(s):  
Ischemia Reperfusion ◽  
Myocardial Necrosis ◽  
In Vivo Model ◽  
Pcr Analysis ◽  
Inos Mrna ◽  
Mrna Levels ◽  
Wild Type ◽  
Significant Difference ◽  
Deficient Mice

Two strains of endothelial nitric oxide synthase (eNOS)-deficient (−/−) mice have been developed that respond differently to myocardial ischemia-reperfusion (MI/R). We evaluated both strains of eNOS−/− mice in an in vivo model of MI/R. Harvard (Har) eNOS−/− mice ( n = 12) experienced an 84% increase in myocardial necrosis compared with wild-type controls ( P < 0.05). University of North Carolina (UNC) eNOS−/−( n = 10) exhibited a 52% reduction in myocardial injury versus wild-type controls ( P < 0.05). PCR analysis of myocardial inducible NO synthase (iNOS) mRNA levels revealed a significant ( P < 0.05) increase in the UNC eNOS−/− mice compared with wild-type mice, and there was no significant difference between the Har eNOS−/− and wild-type mice. UNC eNOS−/− mice treated with an iNOS inhibitor (1400W) exacerbated the extent of myocardial necrosis. When treated with 1400W, Har eNOS−/− did not exhibit a significant increase in myocardial necrosis. These data demonstrate that two distinct strains of eNOS−/− mice display opposite responses to MI/R. Although the protection seen in the UNC eNOS−/− mouse may result from compensatory increases in iNOS, other genes may be involved.

scholarly journals Rolling in P-selectin-deficient mice is reduced but not eliminated in the dorsal skin

Blood ◽  
1995 ◽  
Vol 86 (9) ◽  
pp. 3487-3492 ◽  
Author(s):  
S Yamada ◽  
TN Mayadas ◽  
F Yuan ◽  
DD Wagner ◽  
RO Hynes ◽  
...  
Keyword(s):  
Shear Rate ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Dorsal Skin ◽  
Wild Type ◽  
Significant Difference ◽  
Deficient Mice

P-selectin-mediated rolling is believed to be important in the recruitment of leukocytes to tissue after ischemia-reperfusion injury. The dorsal skin chamber was used to examine differences in the rolling and stable adhesion of circulating leukocytes in subcutaneous (SC) vessels of P-selectin-deficient and age-matched wild-type mice, both under basal conditions and after ischemia-reperfusion. Rolling in the postcapillary venules in SC tissue of P-selectin-deficient mice was significantly lower than that in wild-type mice under the basal conditions and post-ischemia-reperfusion (P < .05), but was not eliminated by the deletion of the P-selectin gene. No significant difference between P-selectin-deficient and wild-type mice in shear rate or leukocyte-endothelial adhesion was observed up to 24 hours after ischemia-reperfusion. These results show that P-selectin-mediated rolling is not a prerequisite for ischemia-reperfusion-induced leukocyte-endothelial adhesion in the skin.

scholarly journals Leukocyte trafficking and myocardial reperfusion injury in ICAM-1/P-selectin-knockout mice

2001 ◽  
Vol 280 (1) ◽  
pp. H60-H67 ◽  
Author(s):  
Stephanie A. Briaud ◽  
Zhi-Ming Ding ◽  
Lloyd H. Michael ◽  
Mark L. Entman ◽  
Sherita Daniel ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Intercellular Adhesion Molecule ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Area At Risk ◽  
Myocardial Ischemia And Reperfusion ◽  
Significant Difference ◽  
Deficient Mice

P-selectin and intercellular adhesion molecule-1 (ICAM-1) mediate early interaction and adhesion of neutrophils to coronary endothelial cells and myocytes after myocardial ischemia and reperfusion. In the present study, we examined the physiological consequences of genetic deletions of ICAM-1 and P-selectin in mice. In wild-type mice, after 1 h of ischemia followed by reperfusion, neutrophil influx into the area of ischemia was increased by 3 h with a peak at 24 h and a decline by 72 h. ICAM-1/P-selectin-deficient mice showed a significant reduction in neutrophils by immunohistochemistry or by myeloperoxidase activity at 24 h but no significant difference at 3 h. Infarct size (area of necrosis/area at risk) assessed 24 h after reperfusion was not different between wild-type and deficient mice after 30 min and 1 h of occlusion. Mice with a deficiency in both ICAM-1 and P-selectin have impaired neutrophil trafficking without a difference in infarct size due to myocardial ischemia-reperfusion.

scholarly journals Environmental tobacco smoke exposure does not prevent corticosteroids reducing inflammation, remodeling, and airway hyperreactivity in mice exposed to allergen

2009 ◽  
Vol 297 (2) ◽  
pp. L380-L387 ◽  
Author(s):  
Dae Jin Song ◽  
Myung Goo Min ◽  
Marina Miller ◽  
Jae Youn Cho ◽  
David H. Broide
Keyword(s):  
Smooth Muscle ◽  
Airway Inflammation ◽  
Environmental Tobacco Smoke ◽  
Tobacco Smoke ◽  
Airway Remodeling ◽  
Muscle Thickness ◽  
Smoke Exposure ◽  
Airway Hyperreactivity ◽  
Tobacco Smoke Exposure ◽  
Mucus Production

The ability of corticosteroids to reduce airway inflammation and improve lung function is significantly reduced in asthmatics who are tobacco smokers compared with asthmatics who are nonsmokers. As not only high levels of tobacco smoke exposure in active smokers, but also significantly lower levels of tobacco smoke exposure from passive environmental tobacco smoke (ETS) exposure in nonsmokers can increase both asthma symptoms and the frequency of asthma exacerbations, we utilized a mouse model to determine whether corticosteroids can reduce levels of airway inflammation, airway remodeling, and airway hyperreactivity in mice exposed to the combination of chronic ETS and ovalbumin (OVA) allergen. Chronic ETS exposure alone did not induce increases in eosinophilic airway inflammation, airway remodeling, or airway hyperreactivity. Mice exposed to chronic OVA allergen had significantly increased levels of peribronchial fibrosis, increased thickening of the smooth muscle layer, increased mucus, and increased airway hyperreactivity, which was significantly enhanced by coexposure to the combination of chronic ETS and chronic OVA allergen. Administration of corticosteroids to mice exposed to chronic ETS and OVA allergen significantly reduced levels of eosinophilic airway inflammation, mucus production, peribronchial smooth muscle thickness, airway hyperreactivity, and the number of peribronchial TGF-β1+ cells. Overall, this study demonstrates that corticosteroids can significantly reduce levels of eosinophilic inflammation, mucus expression, airway remodeling, and airway hyperreactivity in chronic ETS-exposed mice challenged with allergen.

cGMP signals mainly through cAMP kinase in permeabilized murine aorta

2007 ◽  
Vol 292 (1) ◽  
pp. H237-H244 ◽  
Author(s):  
René Wörner ◽  
Robert Lukowski ◽  
Franz Hofmann ◽  
Jörg W. Wegener
Keyword(s):  
Smooth Muscle ◽  
Vascular Tone ◽  
Rho Kinase ◽  
Inhibitory Effect ◽  
Wild Type ◽  
Relaxant Effect ◽  
Aortic Smooth Muscle ◽  
Inhibitor Peptide ◽  
Dependent Protein ◽  
Deficient Mice

GMP affects vascular tone by multiple mechanisms, including inhibition of the Rho/Rho kinase-mediated Ca2+ sensitization, a process identified as Ca2+ desensitization. Ca2+ desensitization is mediated probably by both cGMP- and cAMP-dependent protein kinases (cGKI and PKA). We investigate to which extent Ca2+ desensitization is initiated by cGKI and PKA. cGMP/cAMP-induced relaxation was studied at constant [Ca2+] in permeabilized aortas from wild-type and cGKI-deficient mice. [Ca2+] increased aortic tone in the absence and presence of 50 μM GTPγS with EC50 values of 160 and 30 nM, respectively. In the absence of GTPγS, the EC50 for [Ca2+] was shifted rightward from 0.16 μM to 0.43 and 0.82 μM by 1 and 300 μM 8-bromo-cGMP (8-Br-cGMP), and to 8 μM by 10 μM Y-27632. Contractions induced by 300 nM [Ca2+] were relaxed by 8-Br-cGMP with an EC50 of 2.6 μM. Surprisingly, [Ca2+]-induced contractions were also relaxed by 8-Br-cGMP in aortas from cGKI−/− mice (EC50 of 19 μM). Western blot analysis of the vasodilator-stimulated phosphoprotein indicated “cross”-activation of PKA by 1 mM 8-Br-cGMP in aortic smooth muscle cells from cGKI−/− mice. Indeed, the PKA inhibitor peptide (PKI 5–24) completely abolished the relaxant effect of 8-Br-cGMP in muscles from cGKI−/− mice and to 65% in wild-type aortas. The thromboxane analogue U-46619 induced contraction at constant [Ca2+], which was only partially relaxed by 8-Br-cGMP but completely relaxed by Y-27632. The effect of 8-Br-cGMP on U-46619-induced contraction was attenuated by PKI 5–24. These results show that cGKI has only a small inhibitory effect on Ca2+ sensitization in murine aortas.

Clinical topographical anatomy of the gastro-oesophageal junction in the cat

2017 ◽  
Vol 20 (4) ◽  
pp. 308-311 ◽  
Author(s):  
Agni Voutsinou ◽  
Lysimachos G Papazoglou ◽  
Ioannis Antonopoulos ◽  
Timoleon S Rallis
Keyword(s):  
Smooth Muscle ◽  
Gastric Mucosa ◽  
Abdominal Cavity ◽  
Muscle Thickness ◽  
Muscle Layer ◽  
Smooth Muscle Layer ◽  
Topographical Anatomy ◽  
Transition Level ◽  
The Mean ◽  
High Pressure Zone

Objectives The purpose of the present study was to describe histologically the gastro-oesophageal junction in the cat and interrelationships of this region. Our hypothesis was that cats are devoid of abdominal oesophagus. Methods Three centimetres of the terminal oesophagus, the phreno-oesophageal membrane with 1–2 cm margins of the diaphragmatic crural muscle and the proximal 3 cm of the gastric cardia were obtained from nine domestic shorthair cats and one domestic longhair cat that were euthanased for reasons other than digestive tract pathology. Longitudinal samples were examined histologically. Evaluated parameters included the location of the phreno-oesophageal membrane with reference to the transition between the oesophageal and gastric mucosa, the thickness of the circumferential smooth muscle of the muscular layer of the distal oesophagus at points 3 mm and 6 mm cranial to the mucosa transition, and the thickness of the circumferential smooth muscle layer at the mucosa transition level. Median differences in the thickness of the smooth muscle layer were compared by performing non-parametric statistical analysis using the Mann–Whitney U-test. Results The transition of the oesophageal to gastric mucosa was abrupt and corresponded to the point of insertion of the phreno-oesophageal membrane at the diaphragm level in all cats. The mean thickness of the circumferential smooth muscle layer at the point of oesophageal to gastric mucosa transition was significantly greater than the mean thickness of the oesophageal circumferential smooth muscle layer at 3 mm and 6 mm cranial to the mucosa transition ( P ⩽0.05). The increased muscle thickness at the gastro-oesophageal junction correlates with the accepted location of the high-pressure zone, reflecting the caudal oesophageal sphincter. It seems that the whole oesophagus was situated within the thoracic rather than the abdominal cavity. Conclusions and relevance No distinct abdominal oesophagus was observed in nine domestic shorthair cats and one domestic longhair cat. These findings might have implications for the pathophysiology of hiatal hernia in cats.

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