Negative impact of tissue inhibitor of metalloproteinase-3 null mutation on lung structure and function in response to sepsis

2003 ◽  
Vol 285 (6) ◽  
pp. L1222-L1232 ◽  
Author(s):  
Erica L. Martin ◽  
Brent Z. Moyer ◽  
M. Cynthia Pape ◽  
Barry Starcher ◽  
Kevin J. Leco ◽  
...  
Keyword(s):  
Negative Impact ◽  
Cecal Ligation ◽  
Lung Compliance ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Wild Type ◽  
Gelatinase Activity ◽  
Lung Structure ◽  
And Function ◽  
Knockout Animals

Matrix metalloproteinases (MMPs) are degradative enzymes, which act to remodel tissue. Their activity is regulated by the tissue inhibitors of metalloproteinases (TIMPs). An imbalance in the degradation/inhibition activities has been associated with many diseases, including sepsis. We have previously shown that TIMP-3 knockout animals develop spontaneous, progressive air space enlargement. The objectives of this study were to determine the effects of a septic lung stress induced by cecal ligation and perforation (CLP) on lung function, structure, pulmonary surfactant, and inflammation in TIMP-3 null mice. Knockout and wild-type animals were randomized to either sham or CLP surgery, allowed to recover for 6 h, and then euthanized. TIMP-3 null animals exposed to sham surgery had a significant increase in lung compliance when compared with sham wild-type mice. Additionally, the TIMP-3 knockout mice showed a significant increase in compliance following CLP. Rapid compliance changes were accompanied by significantly decreased collagen and fibronectin levels and increased gelatinase (MMP-2 and -9) abundance and activation. Additionally, in situ zymography showed increased airway-associated gelatinase activity in the knockout animals enhanced following CLP. In conclusion, exposing TIMP-3 null animals to sepsis rapidly enhances the phenotypic abnormalities of these mice, due to increased MMP activity induced by CLP.

scholarly journals Effect of triiodothyronine augmentation on rat lung surfactant phospholipids during sepsis

1997 ◽  
Vol 82 (6) ◽  
pp. 2020-2027 ◽  
Author(s):  
Sergey M. Ksenzenko ◽  
Scott B. Davidson ◽  
Amer A. Saba ◽  
Alexander P. Franko ◽  
Aml M. Raafat ◽  
...  
Keyword(s):  
Lung Surfactant ◽  
Cecal Ligation ◽  
Active Role ◽  
Lung Compliance ◽  
Rat Lung ◽  
Sprague Dawley ◽  
Surfactant Phospholipids ◽  
Surfactant Composition ◽  
And Function

Ksenzenko, Sergey M., Scott B. Davidson, Amer A. Saba, Alexander P. Franko, Aml M. Raafat, Lawrence N. Diebel, and Scott A. Dulchavsky. Effect of triiodothyronine augmentation on rat lung surfactant phospholipids during sepsis. J. Appl. Physiol. 82(6): 2020–2027, 1997.—Surfactant functional effectiveness is dependent on phospholipid compositional integrity; sepsis decreases this through an undefined mechanism. Sepsis-induced hypothyroidism is commensurate and may be related. This study examines the effect of 3,3′,5-triiodo-l-thyronine (T3) supplementation on surfactant composition and function during sepsis. Male Sprague-Dawley rats underwent sham laparotomy (Sham) or cecal ligation and puncture (CLP) with or without T3supplementation [CLP/T3 (3 ng/h)]. After 6, 12, or 24 h, surfactant was obtained by lavage. Function was assessed by a pulsating bubble surfactometer and in vivo compliance studies. Sepsis produced a decrease in surfactant phosphatidylglycerol and phosphatidic acid, with an increase in lesser surface-active lipids phosphatidylserine and phosphatidylinositol. Phosphatidylcholine content was not significantly changed. Sepsis caused an alteration in the fatty acid composition and an increase in saturation in most phospholipids. Hormonal replacement attenuated these changes. Lung compliance and surfactant adsorption were reduced by sepsis and maintained by T3treatment. Thyroid hormone may have an active role in lung functional preservation through maintenance of surfactant homeostasis during sepsis.

Lack of a Requirement for the Inhibitory Fcγ Receptor In IVIG-Mediated Treatment of ITP

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3338-3338
Author(s):  
Danila Leontyev ◽  
Yulia Katsman ◽  
Xue-Zhong Ma ◽  
Donald R. Branch
Keyword(s):  
Knockout Mice ◽  
Conflicts Of Interest ◽  
Inflammatory Diseases ◽  
Ivig Therapy ◽  
Ivig Treatment ◽  
Wild Type ◽  
Fcγ Receptor ◽  
Antiplatelet Antibody ◽  
And Function ◽  
Knockout Animals

Abstract Abstract 3338 One of the most quoted articles in publications and at International meetings regarding the mechanism of intravenous immunoglobulin (IVIg) therapy in autoimmune and inflammatory diseases is that by Samuelsson et al., Science 291, 484 (2001). This article deals with the mechanism of effect of IVIg being due to an increase in the expression and function of the inhibitory Fcγ receptor (FcγRIIB) in splenic macrophages. The conclusions in this Science paper are based primarily on the use of an experimental mouse model of immune thrombocytopenia (ITP) and mice made deficient in FcγRIIB (FcγRIIB-/- knockouts). We have not been able to support these previous findings but instead find the presence of FcγRIIB receptor not necessary for successful treatment of experimental ITP through IVIg treatment. Administration of IVIg to wild-type Balb/c mice previously made thrombocytopenic using an escalating dose of antiplatelet antibody, MWReg30, leads to amelioration of experimental ITP while in untreated mice, platelet counts stay close to nadir. Similar dynamics of the amelioration of ITP were found using splenectomized or FcγRIIB-/- knockout (Taconic Labs) Balb/c mice. However, as previously published (Blood 15, 558 (2003)), IVIg does not work with FcγRIIB-/- knockout mice that are on a mixed B6:129S4 background, obtained from the Jackson Labs. Indeed, B6 (129S4-Fcgr2btm1Rav/J) FcγRIIB-/- knockout mice made thrombocytopenic are completely unresponsive to IVIg treatment. However, surprisingly, when using the recommended control wild-type mice for this knockout, the B6.129SF2 mouse, we found that this wild-type FcγRIIB+/+ mouse also does not respond to IVIg treatment. Confirmation of genotype was done; thus, we suggest that something about the 129S background prevents a response to IVIg therapy and this phenomenon is independent of the FcγRIIB. We have confirmed that wild-type 129S4 mice made thrombocytopenic do not respond to IVIg. We have also examined the B6 FcγRIIB-/- knockout mice from Taconic Labs which are purported to be fully congenic and these mice also do not respond to IVIg. Because of the lack of response to IVIg of wild-type 129S4 mice, we believe that the Taconic B6 FcγRIIB-/- knockout mice may, in fact, be mixed background as are the Jackson mice. Thus, we plan to use SNP protocols for determination of congenicity, comparing C57BL/6 and 129S4 strains to Taconic and Jackson Labs B6 FcγRIIB-/- knockout mice. We expect to show that both B6 FcγRIIB-/- knockout animals are not fully congenic, being a mixture of both C57BL/6 and 129S4 strains. Previous publications that indicated a lack of response to IVIg using FcγRIIB-/- knockout mice either did not test the fully congenic Taconic Balb/c knockouts and/or failed to use the most suitable control animals with the nonfully congenic B6 knockouts, using instead, C57BL/6 wild-type mice which respond well to IVIg treatment. In order to avoid misinterpretation of results, all experiments testing the role for FcγRIIB in the mechanism of IVIg should be done using Taconic Balb/c FcγRIIB-/- knockout mice until congenicity can be established with the B6 knockout animals. These data taken together lead us to the conclusion that the presence of the FcγRIIB receptor is not important for the therapeutic action of IVIg. Disclosures: No relevant conflicts of interest to declare.

Reduced Von Willebrand Factor Secretion Is Associated with Loss of Weibel-Palade Formation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 541-541
Author(s):  
Giancarlo Castaman ◽  
Sofia Helene Giacomelli ◽  
Paula M. Jacobi ◽  
Tobias Obser ◽  
Reinhard Schneppenheim ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Conflicts Of Interest ◽  
Negative Impact ◽  
Von Willebrand Disease ◽  
Hek293 Cells ◽  
Wild Type ◽  
And Function ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 541 Background. Von Willebrand Disease (VWD) is caused by mutations in von Willebrand factor (VWF) that have different pathophysiologic effect in causing low plasma VWF levels. Type 1 VWD includes patients with quantitative plasma VWF deficiency with normal VWF structure and function. Aim of the study. We report three different novel type 1 VWF mutations (A1716P, C2190Y and R2663C) which although located in different VWF domains are associated with reduced secretion and lack of formation of Weibel-Palade body-like granules. Methods. Transient expression of recombinant mutant full-length VWF in 293 EBNA cells was performed and secretion, collagen binding, and GpIb binding assessed in comparison to wild-type VWF. Furthermore, expression was also examined in HEK293 cells that form Weibel-Palade body (WPB)-like granules when transfected with wt VWF. Results. The multimer analysis of plasma VWF was compatible with type 1 VWD. The results of 3 different expression experiments showed a slightly reduced VWF synthesis and drastically impaired secretion into the medium with homozygous expression. In HEK293 cells, homozygous A1716P and C2190Y VWF variants failed to form WPB-like granules, while R2663C was capable of forming granules, but had fewer cells with granules and more with ER-localized VWF. Heterozygous expression of A1716P and C2160Y VWF variants had a negative impact on wild-type VWF and WPB-like granules were observed in transfected cells. Conclusions. Our results demonstrate that homozygous and heterozygous quantitative VWF deficiency caused by missense VWF mutations can be associated with inability to form endothelial Weibel-Palade-like granules and mutations in different VWF domains can affect the formation of these organelles. Disclosures: No relevant conflicts of interest to declare.

Differential response of TIMP-3 null mice to the lung insults of sepsis, mechanical ventilation, and hyperoxia

2005 ◽  
Vol 289 (2) ◽  
pp. L244-L251 ◽  
Author(s):  
Erica L. Martin ◽  
Lynda A. McCaig ◽  
Brent Z. Moyer ◽  
M. Cynthia Pape ◽  
Kevin J. Leco ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Cecal Ligation ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Null Mouse ◽  
Similar Response ◽  
Wild Type ◽  
Air Space ◽  
Different Types ◽  
Insight Into

An imbalance in matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) leads to excessive or insufficient tissue breakdown, which is associated with many disease processes. The TIMP-3 null mouse is a model of MMP/TIMP imbalance, which develops air space enlargement and decreased lung function. These mice responded differently to cecal ligation and perforation (CLP)-induced septic lung injury than wild-type controls. The current study addresses whether the TIMP-3 knockout lung is susceptible to different types of insults or only those involving sepsis, by examining its response to lipopolysaccharide (LPS)-induced sepsis, mechanical ventilation (MV), and hyperoxia. TIMP-3 null noninjured controls of each insult consistently demonstrated significantly higher compliance vs. wild-type mice. Null mice treated with LPS had a further significantly increased compliance compared with untreated controls. Conversely, MV and hyperoxia did not alter compliance in the null lung. MMP abundance and activity increased in response to LPS but were generally unaltered following MV or hyperoxia, correlating with compliance alterations. All three insults produced inflammatory cytokines; however, the response of the null vs. wild-type lung was dependent on the type of insult. Overall, this study demonstrated that 1) LPS-induced sepsis produced a similar response in null mice to CLP-induced sepsis, 2) the null lung responded differently to various insults, and 3) the null susceptibility to compliance changes correlated with increased MMPs. In conclusion, this study provides insight into the role of TIMP-3 in response to various lung insults, specifically its importance in regulating MMPs to maintain compliance during a sepsis.

scholarly journals Lung Compliance and Chronic Obstructive Pulmonary Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
D. Papandrinopoulou ◽  
V. Tzouda ◽  
G. Tsoukalas
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Inflammatory Response ◽  
Pulmonary Disease ◽  
Airflow Obstruction ◽  
Lung Compliance ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Chronic Inflammatory Response ◽  
Lung Structure ◽  
And Function

Chronic obstructive pulmonary disease, namely, pulmonary emphysema and chronic bronchitis, is a chronic inflammatory response of the airways to noxious particles or gases, with resulting pathological and pathophysiological changes in the lung. The main pathophysiological aspects of the disease are airflow obstruction and hyperinflation. The mechanical properties of the respiratory system and its component parts are studied by determining the corresponding volume-pressure (P-V) relationships. The consequences of the inflammatory response on the lung structure and function are depicted on the volume-pressure relationships.

scholarly journals The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

2019 ◽  
Vol 10 (1) ◽  
pp. 199-210 ◽  
Author(s):  
Chuanman Zhou ◽  
Jintao Luo ◽  
Xiaohui He ◽  
Qian Zhou ◽  
Yunxia He ◽  
...  
Keyword(s):  
Plant Hormone ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Loss Of Function ◽  
Wild Type ◽  
C Elegans ◽  
Link Type ◽  
Complex Functions ◽  
And Function ◽  
Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

scholarly journals The Drosophila engrailed and invected Genes: Partners in Regulation, Expression and Function

Genetics ◽  
1996 ◽  
Vol 142 (3) ◽  
pp. 893-906 ◽  
Author(s):  
Elizabeth Gustavson ◽  
Andrew S Goldsborough ◽  
Zehra Ali ◽  
Thomas B Kornberg
Keyword(s):  
Expression Pattern ◽  
Cultured Cells ◽  
Regulatory Region ◽  
Embryonic Lethality ◽  
Wild Type ◽  
Terminal Portion ◽  
Coding Sequence ◽  
Differential Effects ◽  
And Function ◽  
Redundant Functions

Abstract We isolated and characterized numerous engrailed and invected alleles. Among the deficiencies we isolated, a mutant lacking invected sequences was viable and phenotypically normal, a mutant lacking engrailed was an embryo lethal and had slight segmentation defects, and a mutant lacking both engrailed and invected was most severely affected. In seven engrailed alleles, mutations caused translation to terminate prematurely in the central or C-terminal portion of the coding sequence, resulting in embryonic lethality and segmentation defects. Both engrailed and invected expression declined prematurely in these mutant embryos. In wild-type embryos, engrailed and invected are juxtaposed and are expressed in essentially identical patterns. A breakpoint mutant that separates the mgrailed and invected transcription units parceled different aspects of the expression pattern to engrailed or invected. We also found that both genes cause similar defects when expressed ectopically and that the protein products of both genes act to repress transcription in cultured cells. We propose that the varied phenotypes of the engrailed alleles can be explained by the differential effects these mutants have on the combination of engrailed and invected activities, that engrailed and invected share a regulatory region, and that they encode redundant functions.

scholarly journals Negative impact of disuse and unloading on tendon enthesis structure and function

2021 ◽  
Vol 29 ◽  
pp. 46-52
Author(s):  
S. Roffino ◽  
C. Camy ◽  
A. Foucault-Bertaud ◽  
E. Lamy ◽  
M. Pithioux ◽  
...  
Keyword(s):  
Negative Impact ◽  
Structure And Function ◽  
And Function

scholarly journals Rootstocks Overexpressing StNPR1 and StDREB1 Improve Osmotic Stress Tolerance of Wild-Type Scion in Transgrafted Tobacco Plants

2021 ◽  
Vol 22 (16) ◽  
pp. 8398
Author(s):  
Yasmine S. Hezema ◽  
Mukund R. Shukla ◽  
Alok Goel ◽  
Murali M. Ayyanath ◽  
Sherif M. Sherif ◽  
...  
Keyword(s):  
Osmotic Stress ◽  
Transgenic Tobacco ◽  
Physiological Status ◽  
Wild Type ◽  
Long Distance ◽  
Graft Union ◽  
Tobacco Plants ◽  
Osmotic Stress Tolerance ◽  
And Function ◽  
Gene Expression Levels

In grafted plants, the movement of long-distance signals from rootstocks can modulate the development and function of the scion. To understand the mechanisms by which tolerant rootstocks improve scion responses to osmotic stress (OS) conditions, mRNA transport of osmotic responsive genes (ORGs) was evaluated in a tomato/potato heterograft system. In this system, Solanum tuberosum was used as a rootstock and Solanum lycopersicum as a scion. We detected changes in the gene expression levels of 13 out of the 21 ORGs tested in the osmotically stressed plants; of these, only NPR1 transcripts were transported across the graft union under both normal and OS conditions. Importantly, OS increased the abundance of StNPR1 transcripts in the tomato scion. To examine mRNA mobility in transgrafted plants, StNPR1 and StDREB1 genes representing the mobile and non-mobile transcripts, respectively, were overexpressed in tobacco (Nicotiana tabacum). The evaluation of transgenic tobacco plants indicated that overexpression of these genes enhanced the growth and improved the physiological status of transgenic plants growing under OS conditions induced by NaCl, mannitol and polyethylene glycol (PEG). We also found that transgenic tobacco rootstocks increased the OS tolerance of the WT-scion. Indeed, WT scions on transgenic rootstocks had higher ORGs transcript levels than their counterparts on non-transgenic rootstocks. However, neither StNPR1 nor StDREB1 transcripts were transported from the transgenic rootstock to the wild-type (WT) tobacco scion, suggesting that other long-distance signals downstream these transgenes could have moved across the graft union leading to OS tolerance. Overall, our results signify the importance of StNPR1 and StDREB1 as two anticipated candidates for the development of stress-resilient crops through transgrafting technology.

scholarly journals Breeder Diet Strategies for Generating Ttpa-Null and Wild-Type Mice with Low Vitamin E Status to Assess Neurological Outcomes

2020 ◽  
Vol 4 (11) ◽  
Author(s):  
Katherine M Ranard ◽  
Matthew J Kuchan ◽  
John W Erdman
Keyword(s):  
Animal Model ◽  
Vitamin E ◽  
Mouse Model ◽  
Wild Type ◽  
Future Studies ◽  
Neurological Outcomes ◽  
Transfer Protein ◽  
And Function ◽  
The Brain ◽  
Vitamin E Status

ABSTRACT Studying vitamin E [α-tocopherol (α-T)] metabolism and function in the brain and other tissues requires an animal model with low α-T status, such as the transgenic α-T transfer protein (Ttpa)–null (Ttpa−/−) mouse model. Ttpa+/− dams can be used to produce Ttpa−/− and Ttpa+/+mice for these studies. However, the α-T content in Ttpa+/− dams’ diet requires optimization; diets must provide sufficient α-T for reproduction, while minimizing the transfer of α-T to the offspring destined for future studies that require low baseline α-T status. The goal of this work was to assess the effectiveness and feasibility of 2 breeding diet strategies on reproduction outcomes and offspring brain α-T concentrations. These findings will help standardize the breeding methodology used to generate the Ttpa−/− mice for neurological studies.

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