scholarly journals Bleomycin-induced pulmonary injury in mice deficient in SPARC

2000 ◽  
Vol 279 (4) ◽  
pp. L743-L750 ◽  
Author(s):  
Rashmin C. Savani ◽  
Zhao Zhou ◽  
Evguenia Arguiri ◽  
Sunny Wang ◽  
Dinh Vu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Acute Inflammation ◽  
Direct Evidence ◽  
Pulmonary Injury ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
The Matrix ◽  
Chemical Peritonitis ◽  
Deficient Mice ◽  
Wild Type Control

SPARC (secreted protein, acidic and rich in cysteine) is a component of the matrix that appears to regulate tissue remodeling. There is evidence that it accumulates in the lung in the setting of pulmonary injury and fibrosis, but direct evidence of its involvement is only now emerging. We therefore investigated the development of pulmonary fibrosis induced by bleomycin administered either intratracheally or intraperitoneally in mice deficient in SPARC. Bleomycin (0.15 U/mouse) given intratracheally induced significantly more pulmonary fibrosis in mice deficient in SPARC compared with that in wild-type control mice, with the mutant mice demonstrating greater neutrophil accumulation in the lung. However, in wild-type and SPARC-deficient mice given intraperitoneal bleomycin (0.8 U/injection × 5 injections over 14 days), the pattern and severity of pulmonary fibrosis, as well as the levels of leukocyte recruitment, were similar in both strains of mice. These findings suggest that the involvement of SPARC in pulmonary injury is likely to be complex, dependent on several factors including the type, duration, and intensity of the insult. Furthermore, increased neutrophil accumulation in the peritoneal cavity was also observed in SPARC-null mice after acute chemical peritonitis. Together, these data suggest a possible role for SPARC in the recruitment of neutrophils to sites of acute inflammation.

Overlapping Functions of E- and P-Selectin in Neutrophil Recruitment During Acute Inflammation

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2345-2352 ◽  
Author(s):  
Jonathon W. Homeister ◽  
Mengkun Zhang ◽  
Paul S. Frenette ◽  
Richard O. Hynes ◽  
Denisa D. Wagner ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Leukocyte Rolling ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Functional Roles ◽  
Leukocyte Accumulation ◽  
Vascular Bed ◽  
Precise Role ◽  
Wild Type Control

Abstract Selectin adhesion molecules mediate leukocyte rolling on activated endothelium, a prerequisite to leukocyte accumulation at sites of inflammation. The precise role of each selectin (E-, P-, and L-) in this process is unclear and may vary depending on the particular inflammatory stimulus, vascular bed, leukocyte subset, and species; most data suggest discrete functional roles for each selectin. To define the relative roles of E- and P-selectin in mediating neutrophil accumulation in acute dermal inflammation, mice genetically deficient in E-selectin, P-selectin, or both E- and P-selectin were injected intradermally with zymosan. Luminal endothelial expression of E- and P-selectin in response to zymosan was documented in wild-type mice by intravenous administration of fluorochrome-labeled anti–E- and anti–P-selectin antibodies. In mice deficient in E- or P-selectin, neutrophil accumulation was unchanged or only subtly reduced relative to wild-type control mice. In mice deficient in both E- and P-selectin, neutrophil accumulation was significantly reduced (87% at 4 hours and 79% at 8 hours). These data demonstrate that, in this model of acute inflammation, there is considerable overlap in the functions of E- and P-selectin; loss of both selectins was required to impair neutrophil accumulation.

scholarly journals Overlapping Functions of E- and P-Selectin in Neutrophil Recruitment During Acute Inflammation

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2345-2352 ◽  
Author(s):  
Jonathon W. Homeister ◽  
Mengkun Zhang ◽  
Paul S. Frenette ◽  
Richard O. Hynes ◽  
Denisa D. Wagner ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Leukocyte Rolling ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Functional Roles ◽  
Leukocyte Accumulation ◽  
Vascular Bed ◽  
Precise Role ◽  
Wild Type Control

Selectin adhesion molecules mediate leukocyte rolling on activated endothelium, a prerequisite to leukocyte accumulation at sites of inflammation. The precise role of each selectin (E-, P-, and L-) in this process is unclear and may vary depending on the particular inflammatory stimulus, vascular bed, leukocyte subset, and species; most data suggest discrete functional roles for each selectin. To define the relative roles of E- and P-selectin in mediating neutrophil accumulation in acute dermal inflammation, mice genetically deficient in E-selectin, P-selectin, or both E- and P-selectin were injected intradermally with zymosan. Luminal endothelial expression of E- and P-selectin in response to zymosan was documented in wild-type mice by intravenous administration of fluorochrome-labeled anti–E- and anti–P-selectin antibodies. In mice deficient in E- or P-selectin, neutrophil accumulation was unchanged or only subtly reduced relative to wild-type control mice. In mice deficient in both E- and P-selectin, neutrophil accumulation was significantly reduced (87% at 4 hours and 79% at 8 hours). These data demonstrate that, in this model of acute inflammation, there is considerable overlap in the functions of E- and P-selectin; loss of both selectins was required to impair neutrophil accumulation.

scholarly journals Deletion of neutral endopeptidase exacerbates intestinal inflammation induced by Clostridium difficiletoxin A

2001 ◽  
Vol 281 (2) ◽  
pp. G544-G551 ◽  
Author(s):  
Kimberly S. Kirkwood ◽  
Nigel W. Bunnett ◽  
John Maa ◽  
Ignazio Castagliolo ◽  
Bao Liu ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Fluid Secretion ◽  
Neutral Endopeptidase ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Genetic Deletion ◽  
Neurokinin 1

Toxin A (TxA) of Clostridium difficile induces acute inflammation of the intestine initiated by release of substance P (SP) and activation of the neurokinin-1 receptor. However, the mechanisms that terminate this response are unknown. We determined whether the SP-degrading enzyme neutral endopeptidase (NEP, EC 3.4.24.11 ) terminates TxA-induced enteritis. We used both genetic deletion and pharmacological inhibition of NEP to test this hypothesis. In wild-type mice, instillation of TxA (0.5–5 μg) into ileal loops for 3 h dose dependently increased ileal fluid secretion, stimulated granulocyte transmigration determined by myeloperoxidase activity, and caused histological damage characterized by depletion of enterocytes, edema, and neutrophil accumulation. Deletion of NEP reduced the threshold secretory and inflammatory dose of TxA and exacerbated the inflammatory responses by more than twofold. This exacerbated inflammation was prevented by pretreatment with recombinant NEP. Conversely, pretreatment of wild-type mice with the NEP inhibitor phosphoramidon exacerbated enteritis. Thus NEP terminates enteritis induced by C. difficile TxA, underlying the importance of SP degradation in limiting neurogenic inflammation.

scholarly journals Syndecan-4 Inhibits the Development of Pulmonary Fibrosis by Attenuating TGF-β Signaling

2019 ◽  
Vol 20 (20) ◽  
pp. 4989 ◽  
Author(s):  
Yoshinori Tanino ◽  
Xintao Wang ◽  
Takefumi Nikaido ◽  
Kenichi Misa ◽  
Yuki Sato ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Heparan Sulfate ◽  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Lavage Fluid ◽  
Lung Fibroblasts ◽  
Fibrosis Score ◽  
Wild Type ◽  
Deficient Mice

Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4′s critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and α-smooth muscle action (α-SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-β expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-β-induced Smad3 activation, collagen and α-SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-β-induced Smad3 activation and upregulated collagen and α-SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-β signaling.

Exercise Can Reverse the Phenotype of Biglycan Deficient Mice

2003 ◽  
Author(s):  
Joseph M. Wallace ◽  
Rupak M. Rajachar ◽  
Xiao-Dong Chen ◽  
Songtao Shi ◽  
Matthew R. Allen ◽  
...  
Keyword(s):  
Skeletal Development ◽  
Skeletal Growth ◽  
Treadmill Running ◽  
Wild Type ◽  
Connective Tissues ◽  
Cross Sectional ◽  
Age Dependent ◽  
Skeletal Phenotype ◽  
Deficient Mice ◽  
Wild Type Control

Biglycan (Bgn) is a small leucine-rich proteoglycan (SLRP) that is enriched in bone and other skeletal connective tissues and is responsible, in part, for the regulation of postnatal skeletal growth (Bianco, 1990). Mice lacking Bgn display reduced skeletal development and a lower peak bone mass that leads to age-dependent osteopenia (Xu, 1998). We hypothesized that mechanical loading could reverse the skeletal phenotype of Bgn knockout mice. To test this hypothesis, we determined the effects of treadmill running on the geometric, mechanical and mineral properties of Bgn deficient mice bones. After sacrifice, femora and tibiae were tested in 4 point bending and cross-sectional geometric properties and bone mineral parameters were measured. Exercise was able to partially reverse the skeletal phenotype of the Bgn knockouts by increasing both the geometric and mechanical properties of the tibiae to values equal to or greater than those of wild type control mice.

scholarly journals Are B Lymphocytes of Importance in Severe Staphylococcus aureus Infections?

2000 ◽  
Vol 68 (5) ◽  
pp. 2431-2434 ◽  
Author(s):  
Inger Gjertsson ◽  
Olof Hörnquist Hultgren ◽  
Martin Stenson ◽  
Rikard Holmdahl ◽  
Andrzej Tarkowski
Keyword(s):  
Staphylococcus Aureus ◽  
B Cells ◽  
B Cell ◽  
Interleukin 4 ◽  
Wild Type ◽  
Toxic Shock ◽  
Toxic Shock Syndrome Toxin ◽  
Deficient Mice ◽  
Wild Type Control

ABSTRACT To investigate the role of B cells in experimental, superantigen-mediated Staphylococcus aureus arthritis and sepsis, we used gene-targeted B-cell-deficient mice. The mice were inoculated intravenously with a toxic shock syndrome toxin 1 (TSST-1)-producing S. aureus strain. The B-cell-deficient and thus agamma-globulinemic mice showed striking similarities to the wild-type control animals with respect to the development of arthritis, the mortality rate, and the rate of bacterial clearance. Surprisingly, we found that the levels of gamma interferon in serum were significantly lower (P < 0.0001) in B-cell-deficient mice than in the controls, possibly due to impaired superantigen presentation and a diminished expression of costimulatory molecules. In contrast, the levels of interleukin-4 (IL-4), IL-6, and IL-10 in serum were equal in both groups. Our findings demonstrate that neither mature B cells nor their products significantly contribute to the course ofS. aureus-induced septic arthritis.

In Chronic Inflammation, There Exists an IL-6 Independent Pathway for the Induction of Hepcidin.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3205-3205 ◽  
Author(s):  
Seth Rivera ◽  
Victoria Gabayan ◽  
Tomas Ganz
Keyword(s):  
Inflammatory Mediators ◽  
Genetic Background ◽  
Acute Inflammation ◽  
Physiological Model ◽  
Significant Rise ◽  
Wild Type ◽  
And Control ◽  
Deficient Mice ◽  
Anemia Of Inflammation ◽  
Infection Experiments

Abstract The iron regulatory hormone hepcidin is presumed to be the mediator of anemia of inflammation (AI). Patients with hepatic adenomas producing large amounts of hepcidin had severe AI that resolved when the tumors were resected (Weinstein et al, 2002). Patients with disorders associated with AI and mice with acute inflammation also have increased hepcidin. However, hepcidin deficient mice do not develop hypoferremia in response to acute inflammation (Nicolas et al, 2002). We previously showed that IL-6 was necessary for the inflammatory induction of hepcidin and the development of hypoferremia in an acute turpentine model of inflammation (Nemeth et al, 2004). In order to determine whether IL-6 was necessary for the development of AI, we induced chronic peritoneal S. epidermidis abscesses in IL-6 deficient mice (19 with abscesses, 12 controls) and wild type mice with the same genetic background (16 with abscesses, 10 controls). In contrast to our previous results, both IL-6 deficient and wild type mice had a significant rise in hepcidin-1 expression (27.6 vs. 10.9-fold, respectively) but there was no difference between the groups (p=0.939 by 2-way ANOVA). Both IL-6 deficient and control mice demonstrated a similar small but significant fall in hematocrit (49% to 44% vs. 46% to 42%, p=0.538 by 2-way ANOVA) in response to the abscesses. IL-6 is not necessary for the induction of hepcidin or the development of AI in a physiological model of infection. Experiments are underway to define which other inflammatory mediators induce hepcidin.

scholarly journals Endogenous osteopontin promotes ozone-induced neutrophil recruitment to the lungs and airway hyperresponsiveness to methacholine

2013 ◽  
Vol 305 (2) ◽  
pp. L118-L129 ◽  
Author(s):  
Ramon X. Barreno ◽  
Jeremy B. Richards ◽  
Daniel J. Schneider ◽  
Kevin R. Cromar ◽  
Arthur J. Nadas ◽  
...  
Keyword(s):  
Airway Hyperresponsiveness ◽  
Pulmonary Inflammation ◽  
Immunohistochemical Analysis ◽  
Lung Parenchyma ◽  
Lavage Fluid ◽  
Environmental Pollutant ◽  
Forced Oscillation Technique ◽  
Pulmonary Injury ◽  
Wild Type ◽  
Deficient Mice

Inhalation of ozone (O3), a common environmental pollutant, causes pulmonary injury, pulmonary inflammation, and airway hyperresponsiveness (AHR) in healthy individuals and exacerbates many of these same sequelae in individuals with preexisting lung disease. However, the mechanisms underlying these phenomena are poorly understood. Consequently, we sought to determine the contribution of osteopontin (OPN), a hormone and a pleiotropic cytokine, to the development of O3-induced pulmonary injury, pulmonary inflammation, and AHR. To that end, we examined indices of these aforementioned sequelae in mice genetically deficient in OPN and in wild-type, C57BL/6 mice 24 h following the cessation of an acute (3 h) exposure to filtered room air (air) or O3 (2 parts/million). In wild-type mice, O3 exposure increased bronchoalveolar lavage fluid (BALF) OPN, whereas immunohistochemical analysis demonstrated that there were no differences in the number of OPN-positive alveolar macrophages between air- and O3-exposed wild-type mice. O3 exposure also increased BALF epithelial cells, protein, and neutrophils in wild-type and OPN-deficient mice compared with genotype-matched, air-exposed controls. However, following O3 exposure, BALF neutrophils were significantly reduced in OPN-deficient compared with wild-type mice. When airway responsiveness to inhaled acetyl-β-methylcholine chloride (methacholine) was assessed using the forced oscillation technique, O3 exposure caused hyperresponsiveness to methacholine in the airways and lung parenchyma of wild-type mice, but not OPN-deficient mice. These results demonstrate that OPN is increased in the air spaces following acute exposure to O3 and functionally contributes to the development of O3-induced pulmonary inflammation and airway and lung parenchymal hyperresponsiveness to methacholine.

scholarly journals Fas and Fas Ligand Interactions Suppress Melanoma Lung Metastasis

1998 ◽  
Vol 188 (9) ◽  
pp. 1717-1723 ◽  
Author(s):  
Laurie B. Owen-Schaub ◽  
Kenneth L. van Golen ◽  
Laurie L. Hill ◽  
Janet E. Price
Keyword(s):  
Fas Ligand ◽  
Direct Evidence ◽  
Lung Metastases ◽  
Metastatic Tumor ◽  
Metastatic Progression ◽  
Loss Of Function ◽  
Wild Type ◽  
Metastatic Phenotype ◽  
Ligand Interactions ◽  
Deficient Mice

Apoptosis induced by Fas (CD95) ligation is frequently lost during tumor progression; however, there is no direct evidence to support an association of Fas loss-of-function with metastatic tumor behavior. To determine whether Fas loss-of-function is critical for acquisition of the metastatic phenotype, we have compared the ability of Fas-sensitive K1735 murine melanomas to form spontaneous lung metastases in wild-type and Fas ligand–deficient mice. Fas-sensitive melanoma clones are highly tumorigenic but rarely metastatic in wild-type syngeneic mice. However, in Fas ligand–deficient mice, both the incidence and number of metastases are increased. These findings provide the first evidence that Fas–Fas ligand interactions can suppress metastasis and that tumor Fas loss-of-function may be causally linked to metastatic progression.

Epithelial expression of TIMP-1 does not alter sensitivity to bleomycin-induced lung injury in C57BL/6 mice

2008 ◽  
Vol 294 (3) ◽  
pp. L572-L581 ◽  
Author(s):  
Cheryl L. Fattman ◽  
Federica Gambelli ◽  
Gary Hoyle ◽  
Bruce R. Pitt ◽  
Luis A. Ortiz
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Protein C ◽  
Surfactant Protein ◽  
Wild Type ◽  
Surfactant Protein C ◽  
Resistant Strains ◽  
Fibrotic Lung Disease ◽  
Wild Type Control ◽  
Intratracheal Injection

Matrix metalloproteinases (MMPs) are mediators of lung injury, and their activity has been associated with the development of pulmonary fibrosis. To understand how MMPs regulate the development of pulmonary fibrosis, we examined MMP expression in two strains of mice with differing sensitivities to the fibrosis-inducing drug bleomycin. After a single intratracheal injection of the drug, bleomycin-sensitive C57BL/6 mice showed increased expression for MMPs (-2, -7, -9, -13) at both 7 and 14 days posttreatment compared with the bleomycin-resistant BALB/c strain. In addition, TIMP-1, an endogenous inhibitor of MMPs, was upregulated in the lungs of C57BL/6 mice but not BALB/c mice. We designed two strategies to decrease MMP expression to potentially decrease sensitivity of C57BL/6 mice: 1) we engineered C57BL/6 mice that overexpressed TIMP-1 in their lungs via surfactant protein C (SP-C) promoter; and 2) we inhibited expression of MMPs independent of TIMP-1 by knocking out metallothionein (MT), a critical zinc binding protein. SP-C-TIMP-1 mice reduced MMP expression in response to bleomycin. However, they were equally sensitive to bleomycin as their wild-type counterparts, displaying similar levels of hydroxyproline in the lung tissue. MT null mice displayed decreased lung activity of MMPs with no change in TIMP-1. Nonetheless, there was no difference between the MT null and wild-type control littermates with regards to any of the lung injury parameters measured. We conclude that although TIMP-1 expression is differentially regulated in fibrosis-sensitive and fibrosis-resistant strains, epithelial overexpression of TIMP-1 does not appear to substantially alter fibrotic lung disease in mice.

Sign in / Sign up

Export Citation Format

Share Document