Liver proteomics for therapeutic drug discovery: Inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure*

Dear, James W.; Leelahavanichkul, Asada; Aponte, Angel; Hu, Xiaobang; Constant, Stephanie L.; Hewitt, Stephen M.; Yuen, Peter S.T.; Star, Robert A.

doi:10.1097/01.ccm.0000281858.44387.a2

Cited by 44 publications

(28 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Blocking the cyclophilinBsg interaction pharmacologically or by means of an antibody reduces the inflammation responses in a LPS-induced acute lung injury model and a bronchial asthma model in mice. 28,40 Dear et al 41 found that cyclophilin is upregulated in the liver in a sepsis model, and inhibition of Bsg attenuates sepsis-induced AKI. The numbers of labeled (adopted) neutrophils infiltrated into the kidneys after ischemia/reperfusion.…”

Section: Discussionmentioning

confidence: 99%

The E-Selectin Ligand Basigin/CD147 Is Responsible for Neutrophil Recruitment in Renal Ischemia/Reperfusion

Kato¹,

Yuzawa²,

Kosugi³

et al. 2009

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

E-selectin and its ligands are essential for extravasation of leukocytes in inflammation. Here, we report that basigin (Bsg)/CD147 is a ligand for E-selectin that promotes renal inflammation in ischemia/ reperfusion. The selectins and their ligands are essential for leukocyte tethering/rolling on endothelial cells and the initiation of inflammatory response. The selectins are C-type lectins and consist of three members, i.e., P-, L-, and E-selectin. 1,2 P-selectin is expressed upon inflammatory stimulation in platelets and endothelial cells. L-selectin is constitutively expressed on the tip of leukocyte microvilli and implicated in lymphocyte homing to lymph nodes. 3 E-selectin is specifically induced in the endothelium upon inflammatory stimulation. Thus, E-and P-selectin closely collaborate with one another and play a major role in leukocyte recruitment to inflammatory sites. 4 -6 Among the several glycoproteins reported to bind to E-selectin, three have been identified as representative physiologic E-selectin ligands on neutrophils. There are P-selectin glycoprotein ligand-1 (PSGL-1), E-selectin ligand-1, and CD44, and all three play distinct roles during tethering and slow rolling of neutrophils on the endothelium. 7 A minimal recognition motif for all selectins is sialylated and fucosylated glycan determinants, such as sialyl Lewis X, that decorate the terminal extensions of carbohydrates of these molecules. 8,9 However, because of the poor immunogenicity of highly gly-

show abstract

Section: Discussionmentioning

confidence: 99%

The E-Selectin Ligand Basigin/CD147 Is Responsible for Neutrophil Recruitment in Renal Ischemia/Reperfusion

Kato¹,

Yuzawa²,

Kosugi³

et al. 2009

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…Sepsis increases pro-and anti-inflammatory cytokines; the balance between pro-and anti-inflammatory cytokines is associated with severity of sepsis (10, 36, 41, 46, 49). Our group previously reported increases in proinflammatory cytokines TNF-␣ and IL-6 (4, 15, 54, 55) and an anti-inflammatory cytokine IL-10 in our CLP model (3,5,54). Therefore, we determined the therapeutic window for M2AA treatment to reduce CLP-induced increases in the proinflammatory cytokines TNF-␣, IL-6, and IFN-␥ (Fig.…”

Section: B-g and 2)mentioning

confidence: 99%

“…CLP was performed as previously described with some modifications (5,33). Our group (5) has previously reported, as have others (23), that the length of the ligated cecum determines the severity of sepsis and, ultimately, survival, kidney dysfunction (33), and liver damage (3)(4)(5). In this study, we ligated the cecum at 12 mm to obtain a model of moderately severe sepsis.…”

Section: Animalsmentioning

confidence: 99%

Methyl-2-acetamidoacrylate, an ethyl pyruvate analog, decreases sepsis-induced acute kidney injury in mice

Leelahavanichkul

Yasuda²,

Doi³

et al. 2008

American Journal of Physiology-Renal Physiology

Self Cite

View full text Add to dashboard Cite

PS, Star RA. Methyl-2-acetamidoacrylate, an ethyl pyruvate analog, decreases sepsis-induced acute kidney injury in mice. Am J Physiol Renal Physiol 295: F1825-F1835, 2008. First published October 15, 2008 doi:10.1152/ajprenal.90442.2008.-We tested the anti-inflammatory agent methyl-2-acetamidoacrylate (M2AA), an ethyl pyruvate analog, in a cecal ligation-and-puncture (CLP) model of sepsis in CD-1 mice. M2AA administration at the time of CLP improved survival, renal function, kidney histology, liver injury, and splenocyte apoptosis, and lowered cytokine levels (TNF-␣, IL-6, IFN-␥, and IL-10). When M2AA treatment was delayed 6 h (but not 12 h), M2AA still significantly reduced kidney dysfunction, liver injury, splenocyte apoptosis, and cytokine levels. NF-B, a M2AA target, was transiently activated in spleen, peaking at 6 h; kidney and liver NF-B increased steadily with a plateau at 12-24 h. M2AA reduced NF-B activation in spleen at 6 h and in kidney and liver at 24 h. Splenectomy diminished the ability of M2AA to reduce cytokines, especially IL-6, but M2AA still decreased kidney and liver dysfunction, suggesting that splenic NF-B is not central to M2AA action. In contrast, beneficial effects of chloroquine on cytokines and organ damage were neutralized by splenectomy, demonstrating a spleen-specific chloroquine target. Because M2AA and chloroquine act differently, we tested this combination. Survival at 96 h was highest with combination therapy (57%) vs. chloroquine (38%), M2AA (47.6%), or vehicle (5%). The benefit of combination therapy over chloroquine or M2AA alone did not reach statistical significance, indicating potential mechanistic overlap. We conclude that the transient target(s) for M2AA responsible for the narrow 6-h therapeutic window is not splenic NF-B. Identifying this new target and downstream signaling pathways could lengthen the therapeutic window and improve combination therapy with chloroquine. cecal ligation-puncture; spleen; apoptosis; nuclear factor-B; chloroquine THE MORTALITY RATE OF SEPSIS and septic shock remain unacceptably high and have not changed in several decades (9). Approximately 50% of septic patients develop acute kidney injury (AKI) (28, 34). The mortality rate of septic patients with AKI remains as high as 70%, and the development of AKI in septic patients predicts a poor outcome (28). Ethyl pyruvate (EP) is a derivative of an endogenous antioxidant pyruvate (35). EP can scavenge reactive oxygen species and can downregulate proinflammatory cytokines both in vitro and in vivo. EP inhibits high-mobility group box 1 (HMGB1) and decreases the activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-B (NF-B) (35,45,47,51). EP also preserves mucosal histology and permeability after mesenteric ischemia-reperfusion injury (40) and survival and intestinal damage after hemorrhagic shock (42), alcoholic hepatitis (52), and coronary ischemia and reperfusion (50). Previously, our group (2, 33) reported that EP can decrease sepsis-induced AKI and multiple organ failu...

show abstract

“…The urinary CypA concentration was determined by Western blotting, as previously described (22). The team member performing the Western blotting was blinded to which of the four groups the urine sample belonged.…”

Section: Human Studiesmentioning

confidence: 99%

“…CD147 is a receptor that mediates the actions of extracellular CypA [e.g., an anti-CD147 Ab completely prevents CypA-induced chemotaxis of neutrophils (15)]. In vivo, inhibition of CD147 reduces allergic inflammation in mouse models of asthma (14), collagen-induced arthritis (21), and sepsis-induced acute kidney injury (22). Although these in vivo effects have been attributed to CypA antagonism, there are other ligands that activate CD147, such as E-selectin (23).…”

mentioning

confidence: 99%

Cyclophilin A Is a Damage-Associated Molecular Pattern Molecule That Mediates Acetaminophen-Induced Liver Injury

Dear

Simpson

Nicolai

et al. 2011

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The immune system is alerted to cell death by molecules known as damage-associated molecular patterns (DAMPs). These molecules partly mediate acetaminophen-induced liver injury, an archetypal experimental model of sterile cell death and the commonest cause of acute liver failure in the western world. Cyclophilin A (CypA) is an intracellular protein that is proinflammatory when released by cells. We hypothesized that CypA is released from necrotic liver cells and acts as a DAMP to mediate acetaminophen-induced liver injury. Our data demonstrated that mice lacking CypA (Ppia−/−) were resistant to acetaminophen toxicity. Antagonism of the extracellular receptor for CypA (CD147) also reduced acetaminophen-induced liver injury. When injected into a wild-type mouse, necrotic liver from Ppia−/− mice induced less of an inflammatory response than did wild-type liver. Conversely, the host inflammatory response was increased when CypA was injected with necrotic liver. Antagonism of CD147 also reduced the inflammatory response to necrotic liver. In humans, urinary CypA concentration was significantly increased in patients with acetaminophen-induced liver injury. In summary, CypA is a DAMP that mediates acetaminophen poisoning. This mechanistic insight presents an opportunity for a new therapeutic approach to a disease that currently has inadequate treatment options.

show abstract

Liver proteomics for therapeutic drug discovery: Inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure*

Cited by 44 publications

References 34 publications

The E-Selectin Ligand Basigin/CD147 Is Responsible for Neutrophil Recruitment in Renal Ischemia/Reperfusion

The E-Selectin Ligand Basigin/CD147 Is Responsible for Neutrophil Recruitment in Renal Ischemia/Reperfusion

Methyl-2-acetamidoacrylate, an ethyl pyruvate analog, decreases sepsis-induced acute kidney injury in mice

Cyclophilin A Is a Damage-Associated Molecular Pattern Molecule That Mediates Acetaminophen-Induced Liver Injury

Contact Info

Product

Resources

About