scholarly journals Skeletal muscle reperfusion injury is mediated by neutrophils and the complement membrane attack complex

1999 ◽  
Vol 277 (6) ◽  
pp. C1263-C1268 ◽  
Author(s):  
Constantinos Kyriakides ◽  
William Austen ◽  
Yong Wang ◽  
Joanne Favuzza ◽  
Lester Kobzik ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Reperfusion Injury ◽  
Membrane Attack Complex ◽  
Wild Type ◽  
Complement Components ◽  
Neutrophil Activity ◽  
Deficient Mice ◽  
Terminal Complement

The relative inflammatory roles of neutrophils, selectins, and terminal complement components are investigated in this study of skeletal muscle reperfusion injury. Mice underwent 2 h of hindlimb ischemia followed by 3 h of reperfusion. The role of neutrophils was defined by immunodepletion, which reduced injury by 38%, as did anti-selectin therapy with recombinant soluble P-selectin glycoprotein ligand-immunoglobulin (Ig) fusion protein. Injury in C5-deficient and soluble complement receptor type 1-treated wild-type mice was 48% less than that of untreated wild-type animals. Injury was restored in C5-deficient mice reconstituted with wild-type serum, indicating the effector role of C5–9. Neutropenic C5-deficient animals showed additive reduction in injuries (71%), which was lower than C5-deficient neutrophil-replete mice, indicating neutrophil activity without C5a. Hindlimb histological injury was worse in ischemic wild-type and C5-deficient animals reconstituted with wild-type serum. In conclusion, the membrane attack complex and neutrophils act additively to mediate skeletal muscle reperfusion injury. Neutrophil activity is independent of C5a but is dependent on selectin-mediated adhesion.

Membrane attack complex of complement and neutrophils mediate the injury of acid aspiration

1999 ◽  
Vol 87 (6) ◽  
pp. 2357-2361 ◽  
Author(s):  
Constantinos Kyriakides ◽  
William Austen ◽  
Yong Wang ◽  
Joanne Favuzza ◽  
Lester Kobzik ◽  
...  
Keyword(s):  
Membrane Attack Complex ◽  
Receptor Type ◽  
Complement Receptor ◽  
Wild Type ◽  
Acid Aspiration ◽  
Complement Receptor Type ◽  
Deficient Mice ◽  
Complement Receptor Type 1

A significant role for the alternative complement pathway in acid aspiration has been demonstrated by the observation that C3 genetic knockout mice are protected from injury. Utilizing C5-deficient mice, we now test the role of the terminal complement components in mediating injury. Lung permeability in C5-deficient mice was 64% less than in wild-type animals and was similar to wild-type mice treated with soluble complement receptor type 1, which gave a 67% protection. Injury was fully restored in C5-deficient mice reconstituted with wild-type serum. The role of neutrophils was established in immunodepleted wild-type animals that showed a 58% protection. Injury was further reduced (90%) with the addition of soluble complement receptor type 1, indicating an additive effect of neutrophils and complement. Similarly, an additional protection was noted in C5-deficient neutropenic mice, indicating that neutrophil-mediated injury does not require C5a. Thus acid aspiration injury is mediated by the membrane attack complex and neutrophils. Neutrophil activity is independent of C5a.

Role of α/β and γ/δ T cells in renal ischemia-reperfusion injury

2007 ◽  
Vol 293 (3) ◽  
pp. F741-F747 ◽  
Author(s):  
Kathrin Hochegger ◽  
Tobias Schätz ◽  
Philipp Eller ◽  
Andrea Tagwerker ◽  
Dorothea Heininger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Wild Type ◽  
Renal Ischemia Reperfusion Injury ◽  
Deficient Mice

T cells have been implicated in the pathogenesis of renal ischemia-reperfusion injury (IRI). To date existing data about the role of the T cell receptor (Tcr) are contradictory. We hypothesize that the Tcr plays a prominent role in the late phase of renal IRI. Therefore, renal IRI was induced in α/β, γ/δ T cell-deficient and wild-type mice by clamping renal pedicles for 30 min and reperfusing for 24, 48, 72, and 120 h. Serum creatinine increased equally in all three groups 24 h after ischemia but significantly improved in Tcr-deficient animals compared with wild-type controls after 72 h. A significant reduction in renal tubular injury and infiltration of CD4+ T-cells in both Tcr-deficient mice compared with wild-type controls was detected. Infiltration of α/β T cells into the kidney was reduced in γ/δ T cell-deficient mice until 72 h after ischemia. In contrast, γ/δ T cell infiltration was equal in wild-type and α/β T cell-deficient mice, suggesting an interaction between α/β and γ/δ T cells. Data from γ/δ T cell-deficient mice were confirmed by in vivo depletion of γ/δ T cells in C57BL/6 mice. Whereas α/β T cell-deficient mice were still protected after 120 h, γ/δ T cell-deficient mice showed a “delayed wild-type phenotype” with a dramatic increase in kidney-infiltrating α/β, Tcr-expressing CD4+ T-cells. This report provides further evidence that α/β T cells are major effector cells in renal IRI, whereas γ/δ T cells play a role as mediator cells in the first 72 h of renal IRI.

scholarly journals Intercellular crosstalk regulating ARRB2/RARRES1 is involved in transition from fibrosis to cancer

2021 ◽  
Author(s):  
Robert Schierwagen ◽  
Peter Dietrich ◽  
Judith Heinzen ◽  
Sabine Klein ◽  
Frank E. Uschner ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Retinoic Acid ◽  
Liver Tumors ◽  
Retinoic Acid Receptor ◽  
Cancer Development ◽  
Wild Type ◽  
Chronic Liver Injury ◽  
Deficient Mice

AbstractProgressive fibrogenesis in chronic liver injury is often associated with cancer development. Beta-arrestin-2 (ARRB2) is a regulator of the profibrotic Angiotensin II type 1 receptor (AGTR1). The role of ARRB2 in liver fibrosis and in the transition from fibrosis to cancer is not fully understood and was investigated in this study.This study demonstrates that upregulation of the retinoic acid receptor responder 1 (RARRES1) in HSC mediated by ARRB2 leads to fibrosis. This process is driven by exosomal ARRB2 transfer to HSC, major fibrosis contributors, from injured hepatocytes, which highly express ARRB2. By contrast, downregulation of RARRES1 in hepatocytes induces malignant transformation and hepatocellular carcinoma (HCC) development. Consequently, Arrb2-deficient mice show higher number and size of liver tumors than wild-type mice in a hepatocellular carcinoma model with fibrosis. The identified relationship between ARRB2 and RARRES1 was observed in at least two species, including human cells and tissues in fibrosis and HCC and has a predictive value for survival in cancer patients. This study describes the discovery of a novel molecular pathway mediating the transition from fibrosis to cancer offering potential diagnostics and therapeutics.

scholarly journals The Type 1 Insulin-Like Growth Factor Receptor (IGF-IR) Pathway Is Mandatory for the Follistatin-Induced Skeletal Muscle Hypertrophy

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 241-253 ◽  
Author(s):  
S. Kalista ◽  
O. Schakman ◽  
H. Gilson ◽  
P. Lause ◽  
B. Demeulder ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Knockout Mice ◽  
Muscle Hypertrophy ◽  
Critical Role ◽  
Muscle Growth ◽  
Dominant Negative ◽  
Wild Type ◽  
Myostatin Inhibition

Myostatin inhibition by follistatin (FS) offers a new approach for muscle mass enhancement. The aim of the present study was to characterize the mediators responsible for the FS hypertrophic action on skeletal muscle in male mice. Because IGF-I and IGF-II, two crucial skeletal muscle growth factors, are induced by myostatin inhibition, we assessed their role in FS action. First, we tested whether type 1 IGF receptor (IGF-IR) is required for FS-induced hypertrophy. By using mice expressing a dominant-negative IGF-IR in skeletal muscle, we showed that IGF-IR inhibition blunted by 63% fiber hypertrophy caused by FS. Second, we showed that FS caused the same degree of fiber hypertrophy in wild-type and IGF-II knockout mice. We then tested the role of the signaling molecules stimulated by IGF-IR, in particular the Akt/mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (S6K) pathway. We investigated whether Akt phosphorylation is required for the FS action. By cotransfecting a dominant-negative form of Akt together with FS, we showed that Akt inhibition reduced by 65% fiber hypertrophy caused by FS. Second, we evaluated the role of mTOR in FS action. Fiber hypertrophy induced by FS was reduced by 36% in rapamycin-treated mice. Finally, because the activity of S6K is increased by FS, we tested its role in FS action. FS caused the same degree of fiber hypertrophy in wild-type and S6K1/2 knockout mice. In conclusion, the IGF-IR/Akt/mTOR pathway plays a critical role in FS-induced muscle hypertrophy. In contrast, induction of IGF-II expression and S6K activity by FS are not required for the hypertrophic action of FS.

Moderation of skeletal muscle reperfusion injury by a sLex-glycosylated complement inhibitory protein

2001 ◽  
Vol 281 (1) ◽  
pp. C224-C230 ◽  
Author(s):  
Constantinos Kyriakides ◽  
Yong Wang ◽  
William G. Austen ◽  
Joanne Favuzza ◽  
Lester Kobzik ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Reperfusion Injury ◽  
Vascular Endothelium ◽  
Hindlimb Ischemia ◽  
Permeability Index ◽  
Inhibitory Protein ◽  
Sialyl Lewis ◽  
Neutrophil Depletion

The role of the sialyl Lewisx(sLex)-decorated version of soluble complement receptor type 1 (sCR1) in moderating skeletal muscle reperfusion injury, by antagonizing neutrophil endothelial selectin interaction and complement activation, is examined. Mice underwent 2 h of hindlimb ischemia and 3 h of reperfusion. Permeability index (PI) was assessed by extravasation of125I-labeled albumin. Neutrophil depletion and complement inhibition with sCR1 reduced permeability by 72% (PI 0.81 ± 0.10) compared with a 42% decrease (PI 1.53 ± 0.08) observed in neutropenic mice, indicating that part of the complement-mediated injury is neutrophil independent. sCR1sLextreatment reduced PI by 70% (PI 0.86 ± 0.06), an additional 20% decrease compared with sCR1 treatment (PI 1.32 ± 0.08). Treatment with sCR1sLex0.5 and 1 h after reperfusion reduced permeability by 63% (PI 0.09 ± 0.07) and 52% (PI 1.24 ± 0.09), respectively, compared with the respective decreases of 41% (PI 1.41 ± 0.10) and 32% (PI 1.61 ± 0.07) after sCR1 treatment. Muscle immunohistochemistry stained for sCR1 only on the vascular endothelium of sCR1sLex-treated mice. In conclusion, sCR1sLexis more effective than sCR1 in moderating skeletal muscle reperfusion injury.

scholarly journals Role of Complement in Protection against Cryptococcus gattii Infection

2008 ◽  
Vol 77 (3) ◽  
pp. 1061-1070 ◽  
Author(s):  
Kileen L. Mershon ◽  
Alex Vasuthasawat ◽  
Gregory W. Lawson ◽  
Sherie L. Morrison ◽  
David O. Beenhouwer
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Complement Pathway ◽  
Wild Type ◽  
Complement Components ◽  
Factor B ◽  
Alternative Pathway Of Complement ◽  
Deficient Mice

ABSTRACT Previous studies have shown that the alternative pathway of complement activation plays an important role in protection against infection with Cryptococcus neoformans. Cryptococcus gattii does not activate the alternative pathway as well as C. neoformans in vitro. The role of complement in C. gattii infection in vivo has not been reported. In this study, we used mice deficient in complement components to investigate the role of complement in protection against a C. gattii isolate from an ongoing outbreak in northwestern North America. While factor B-deficient mice showed an enhanced rate of death, complement component C3-deficient mice died even more rapidly, indicating that the alternative pathway was not the only complement pathway contributing to protection against disease. Both C3- and factor B-deficient mice had increased fungal burdens in comparison to wild-type mice. Histopathology revealed an overwhelming fungal burden in the lungs of these complement-deficient mice, which undoubtedly prevented efficient gas exchange, causing death. Following the fate of radiolabeled organisms showed that both factor B- and C3-deficient mice were less effective than wild-type mice in clearing organisms. However, opsonization of C. gattii with complement components was not sufficient to prolong life in mice deficient in complement. Killing of C. gattii by macrophages in vitro was decreased in the presence of serum from factor B- and C3-deficient versus wild-type mice. In conclusion, we have demonstrated that complement activation is crucial for survival in C. gattii infection. Additionally, we have shown that the alternative pathway of complement activation is not the only complement pathway contributing to protection.

scholarly journals Alteration of Sarcoplasmic ReticulumCa2+Release in Skeletal Muscle from Calpain 3-Deficient Mice

2009 ◽  
Vol 2009 ◽  
pp. 1-12 ◽  
Author(s):  
Govindan Dayanithi ◽  
Isabelle Richard ◽  
Cédric Viero ◽  
Elsa Mazuc ◽  
Sylvie Mallie ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Cellular Differentiation ◽  
Cyclopiazonic Acid ◽  
Skeletal Muscle Regeneration ◽  
Muscular Dystrophies ◽  
Wild Type ◽  
Calpain 3 ◽  
Deficient Mice

Mutations ofCa2+-activated proteases (calpains) cause muscular dystrophies. Nevertheless, the specific role of calpains inCa2+signalling during the onset of dystrophies remains unclear. We investigatedCa2+handling in skeletal cells from calpain 3-deficient mice.[Ca2+]iresponses to caffeine, a ryanodine receptor (RyR) agonist, were decreased in −/− myotubes and absent in −/− myoblasts. The −/− myotubes displayed smaller amplitudes of theCa2+transients induced by cyclopiazonic acid in comparison to wild type cells. Inhibition of L-typeCa2+channels (LCC) suppressed the caffeine-induced[Ca2+]iresponses in −/− myotubes. Hence, the absence of calpain 3 modifies the sarcoplasmic reticulum (SR)Ca2+release, by a decrease of the SR content, an impairment of RyR signalling, and an increase of LCC activity. We propose that calpain 3-dependent proteolysis plays a role in activating support proteins of intracellularCa2+signalling at a stage of cellular differentiation which is crucial for skeletal muscle regeneration.

scholarly journals Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4+ T Cell Responses during Chronic Helicobacter pylori Infection

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Adria Carbo ◽  
Danyvid Olivares-Villagómez ◽  
Raquel Hontecillas ◽  
Josep Bassaganya-Riera ◽  
Rupesh Chaturvedi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Wild Type ◽  
Content Type ◽  
Interleukin 21 ◽  
H Pylori ◽  
Deficient Mice

ABSTRACTThe development of gastritis duringHelicobacter pyloriinfection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. pyloriinfection, we combined mathematical modeling of CD4+T cell differentiation within vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pyloristrain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. pyloricolonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. Thesein vivodata were used to calibrate anH. pyloriinfection-dependent, CD4+T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronicH. pyloriinfection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+splenocyte-specifictbx21androrcexpression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+T cell-specific IL-10 expression inH. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronicH. pyloriinfection in a STAT1- and STAT3-dependent manner, therefore playing a major role controllingH. pyloriinfection and gastritis.IMPORTANCEHelicobacter pyloriis the dominant member of the gastric microbiota in more than 50% of the world’s population.H. pyloricolonization has been implicated in gastritis and gastric cancer, as infection withH. pyloriis the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis duringH. pyloriinfection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized withH. pylorias an alternative to aggressive antibiotics.

AMP kinase is not required for the GLUT4 response to exercise and denervation in skeletal muscle

2004 ◽  
Vol 287 (4) ◽  
pp. E739-E743 ◽  
Author(s):  
Burton F. Holmes ◽  
David B. Lang ◽  
Morris J. Birnbaum ◽  
James Mu ◽  
G. Lynis Dohm
Keyword(s):  
Skeletal Muscle ◽  
Dominant Negative ◽  
Treadmill Running ◽  
Wild Type ◽  
Α Subunit ◽  
Ampk Activity ◽  
Denervated Muscles ◽  
Amp Activated Protein Kinase ◽  
Response To Exercise

An acute bout of exercise increases muscle GLUT4 mRNA in mice, and denervation decreases GLUT4 mRNA. AMP-activated protein kinase (AMPK) activity in skeletal muscle is also increased by exercise, and GLUT4 mRNA is increased in mouse skeletal muscle after treatment with AMPK activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside(AICAR). These findings suggest that AMPK activation might be responsible for the increase in GLUT4 mRNA expression in response to exercise. To investigate the role of AMPK in GLUT4 regulation in response to exercise and denervation, transgenic mice with a mutated AMPK α-subunit (dominant negative; AMPK-DN) were studied. GLUT4 did not increase in AMPK-DN mice that were treated with AICAR, demonstrating that muscle AMPK is inactive. Exercise (two 3-h bouts of treadmill running separated by 1 h of rest) increased GLUT4 mRNA in both wild-type and AMPK-DN mice. Likewise, denervation decreased GLUT4 mRNA in both wild-type and AMPK-DN mice. GLUT4 mRNA was also increased by AICAR treatment in both the innervated and denervated muscles. These data demonstrate that AMPK is not required for the response of GLUT4 mRNA to exercise and denervation.

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