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BETA
Zheng, Limin
Alternative names
Publications (10 of 15) Show all publications
Blomgran, R., Zheng, L. & Stendahl, O. (2007). Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization. Journal of Leukocyte Biology, 81, 1213-1223
Open this publication in new window or tab >>Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization
2007 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 81, p. 1213-1223Article in journal (Refereed) Published
Abstract [en]

Lysosomal membrane permeabilization (LMP) is emerging as an important regulator of cell apoptosis. Human neutrophils are highly granulated phagocytes, which respond to pathogens by exhibiting increased production of reactive oxygen species (ROS) and lysosomal degranulation. In a previous study, we observed that intracellular, nonphagosomal generation of ROS triggered by adherent bacteria induced ROS-dependent neutrophil apoptosis, whereas intraphagosomal production of ROS during phagocytosis had no effect. In the present study, we measured lysosomal membrane stability and leakage in human neutrophils and found that adherent, noningested, Type 1-fimbriated Escherichia coli bacteria induced LMP rapidly in neutrophils. Pretreatment with the NADPH oxidase inhibitor diphenylene iodonium markedly blocked the early LMP and apoptosis in neutrophils stimulated with Type 1-fimbriated bacteria but had no effect on the late LMP seen in spontaneously apoptotic neutrophils. The induced lysosomal destabilization triggered cleavage of the proapoptotic Bcl-2 protein Bid, followed by a decrease in the antiapoptotic protein Mcl-1. Involvement of LMP in initiation of apoptosis is supported by the following observations: Bid cleavage and the concomitant drop in mitochondrial membrane potential required activation of cysteine-cathepsins but not caspases, and the differential effects of inhibitors of cysteine-cathepsins and cathepsin D on apoptosis coincided with their ability to inhibit Bid cleavage in activated neutrophils. Together, these results indicate that in microbe-induced apoptosis in neutrophils, ROS-dependent LMP represents an early event in initiation of the intrinsic apoptotic pathway, which is followed by Bid cleavage, mitochondrial damage, and caspase activation.

Keywords
bacteria, Bcl-2 family proteins, Escherichia coli, lysosomes, Mcl-1, reactive oxygen species
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14005 (URN)doi:10.1189/jlb.0506359 (DOI)
Available from: 2006-09-27 Created: 2006-09-27 Last updated: 2017-12-13
Wang, J., Zheng, L. & Walther, S. (2004). Administration of aerosolized terbutaline and budesonide reduces chlorine gas-induced acute lung injury. Journal of Trauma, 56(4), 850-862
Open this publication in new window or tab >>Administration of aerosolized terbutaline and budesonide reduces chlorine gas-induced acute lung injury
2004 (English)In: Journal of Trauma, ISSN 0022-5282, E-ISSN 1529-8809, Vol. 56, no 4, p. 850-862Article in journal (Refereed) Published
Abstract [en]

Background: The pathophysiology and treatment of chlorine gas-induced acute lung injury is poorly characterized and based on anecdotal data. This study aimed to assess the effects of aerosolized beta-2 adrenergic agonist and corticosteroid therapy on chlorine gas-induced lung injury.

Methods: Anesthetized, ventilated pigs were exposed to chlorine gas (400 parts per million for 20 minutes), then assigned randomly 30 minutes later to receive aerosolized terbutaline, budesonide, terbutaline followed by budesonide or placebo (6 pigs in each group). Hemodynamics, gas exchange, and lung mechanics were evaluated for another 5 hours.

Results: All the animals demonstrated an immediate increase in airway and pulmonary artery pressure as well as sharp drops in arterial oxygen tension (PaO2) and lung compliance (C L). Recovery of PaO2 and CL was greatest in the terbutaline plus budesonide group, but therapy with terbutaline and budesonide alone also was associated with significant improvement in PaO2 and CL, as compared with placebo.

Conclusions. Treatment of acute chlorine gas lung injury with aerosolized terbutaline followed by aerosolized budesonide improved lung function. Combined treatment was more effective than treatment with either drug alone.

Keywords
acute lung injury, aerosol, chlorine gas, beta-2-adrenergic agonist, corticosteroid, experimental study, lung function
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-46235 (URN)10.1097/01.TA.0000078689.45384.8B (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
Zheng, L., He, M., Long, M., Blomgran, R. & Stendahl, O. (2004). Pathogen-Induced Apoptotic Neutrophils Express Heat Shock Proteins and Elicit Activation of Human Macrophages. Journal of immunology, 173(10), 6319-6326
Open this publication in new window or tab >>Pathogen-Induced Apoptotic Neutrophils Express Heat Shock Proteins and Elicit Activation of Human Macrophages
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2004 (English)In: Journal of immunology, ISSN 0022-1767, Vol. 173, no 10, p. 6319-6326Article in journal (Refereed) Published
Abstract [en]

Ingestion of aged or irradiated apoptotic neutrophils actively suppresses stimulation of macrophages (MΦ). Many bacterial pathogens can also provoke apoptosis in neutrophils, but little is known about how such apoptotic cells influence MΦ activation. We found that neutrophils undergoing apoptosis induced by UV irradiation, Escherichia coli, or Staphylococcus aureus could either stimulate or inhibit MΦ activation. In contrast to MΦ that had ingested irradiated apoptotic neutrophils, MΦ that had phagocytosed bacteria-induced apoptotic neutrophils exhibited markedly increased production of the proinflammatory cytokine TNF-α, but not the anti-inflammatory cytokine TGF-β. Moreover, ingestion of bacteria, but not UV-induced apoptotic neutrophils, caused increased expression of FcγRI on MΦ, and this effect was not provoked directly by bacteria associated with the apoptotic neutrophils. Instead, we found that a link between pathogen-induced apoptotic neutrophils and up-regulation of the heat shock proteins HSP60 and HSP70, and we also observed that recombinant HSP60 and HSP70 potentiated LPS-stimulated production of TNF-α in MΦ. The opposing macrophage responses to neutrophils undergoing apoptosis induced in different ways may represent a novel mechanism that regulates the extent of the immune response to invading microbes in two steps: first by aiding the functions of MΦ at an early stage of infection, and subsequently by deactivating those cells through removal of uninfected apoptotic neutrophils. HSP induction in neutrophils may provide the danger signals required to generate a more effective macrophage response.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14006 (URN)
Available from: 2006-09-27 Created: 2006-09-27 Last updated: 2009-06-09
Blomgran, R., Zheng, L. & Stendahl, O. (2004). Uropathogenic Escherichia coli triggers oxygen-dependent apoptosis in human neutrophils through the cooperative effect of type 1 fimbriae and lipopolysaccharide. Infection and Immunity, 72(8), 4570-4578
Open this publication in new window or tab >>Uropathogenic Escherichia coli triggers oxygen-dependent apoptosis in human neutrophils through the cooperative effect of type 1 fimbriae and lipopolysaccharide
2004 (English)In: Infection and Immunity, ISSN 0019-9567, Vol. 72, no 8, p. 4570-4578Article in journal (Refereed) Published
Abstract [en]

Type 1 fimbriae are the most commonly expressed virulence factor on uropathogenic Escherichia coli. In addition to promoting avid bacterial adherence to the uroepithelium and enabling colonization, type 1 fimbriae recruit neutrophils to the urinary tract as an early inflammatory response. Using clinical isolates of type 1 fimbriated E. coli and an isogenic type 1 fimbria-negative mutant (CN1016) lacking the FimH adhesin, we investigated if these strains could modulate apoptosis in human neutrophils. We found that E. coli expressing type 1 fimbriae interacted with neutrophils in a mannose- and lipopolysaccharide (LPS)-dependent manner, leading to apoptosis which was triggered by the intracellular generation of reactive oxygen species. This induced neutrophil apoptosis was abolished by blocking FimH-mediated attachment, by inhibiting NADPH oxidase activation, or by neutralizing LPS. In contrast, CN1016, which did not adhere to or activate the respiratory burst of neutrophils, delayed the spontaneous apoptosis in an LPS-dependent manner. This delayed apoptosis could be mimicked by adding purified LPS and was also observed by using fimbriated bacteria in the presence of D-mannose. These results suggest that LPS is required for E. coli to exert both pro- and antiapoptotic effects on neutrophils and that the difference in LPS presentation (i.e., with or without fimbriae) determines the outcome. The present study showed that there is a fine-tuned balance between type 1 fimbria-induced and LPS-mediated delay of apoptosis in human neutrophils, in which altered fimbrial expression on uropathogenic E. coli determines the neutrophil survival and the subsequent inflammation during urinary tract infections.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14004 (URN)10.1128/IAI.72.8.4570-4578.2004 (DOI)
Available from: 2006-09-27 Created: 2006-09-27 Last updated: 2009-04-28
Forsberg, M., Druid, P., Zheng, L., Stendahl, O. & Särndahl, E. (2003). Activation of Rac2 and Cdc42 on Fc and complement receptor ligation in human neutrophils. Journal of Leukocyte Biology, 74(4), 611-619
Open this publication in new window or tab >>Activation of Rac2 and Cdc42 on Fc and complement receptor ligation in human neutrophils
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2003 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 74, no 4, p. 611-619Article in journal (Refereed) Published
Abstract [en]

Phagocytosis is a complex process engaging a concerted action of signal-transduction cascades that leads to ingestion, subsequent phagolysosome fusion, and oxidative activation. We have previously shown that in human neutrophils, C3bi-mediated phagocytosis elicits a significant oxidative response, suggesting that activation of the small GTPase Rac is involved in this process. This is contradictory to macrophages, where only Fc receptor for immunoglobulin G (FcγR)-mediated activation is Rac-dependent. The present study shows that engagement of the complement receptor 3 (CR3) and FcγR and CR3- and FcγR-mediated phagocytosis activates Rac, as well as Cdc42. Furthermore, following receptor-engagement of the CR3 or FcγRs, a downstream target of these small GTPases, p21-activated kinase, becomes phosphorylated, and Rac2 is translocated to the membrane fraction. Using the methyltransferase inhibitors N-acetyl-S-farnesyl-L-cysteine and N-acetyl-S-geranylgeranyl-L-cysteine, we found that the phagocytic uptake of bacteria was not Rac2- or Cdc42-dependent, whereas the oxidative activation was decreased. In conclusion, our results indicate that in neutrophils, Rac2 and Cdc42 are involved in FcR- and CR3-induced activation and for properly functioning signal transduction involved in the generation of oxygen radicals.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24991 (URN)10.1189/jlb.1102525 (DOI)9411 (Local ID)9411 (Archive number)9411 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
Forsberg, M., Blomgran, R., Lem, M., Särndahl, E., Sebti, S. M., Hamilton, A., . . . Zheng, L. (2003). Differential effects of invasion by and phagocytosis of Salmonella typhimurium on apoptosis in human macrophages: potential role of Rho–GTPases and Akt. Journal of Leukocyte Biology, 74(4), 620-629
Open this publication in new window or tab >>Differential effects of invasion by and phagocytosis of Salmonella typhimurium on apoptosis in human macrophages: potential role of Rho–GTPases and Akt
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2003 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 74, no 4, p. 620-629Article in journal (Refereed) Published
Abstract [en]

In addition to direct activation of caspase-1 and induction of apoptosis by SipB, invasive Salmonella stimulates multiple signaling pathways that are key regulators of host cell survival. Nevertheless, little is known about the relative contributions of these pathways to Salmonella-mediated death of macrophages. We studied human monocytic U937 cells and found that apoptosis was induced by invading wild-type Salmonella typhimurium but not by phagocytosed, serum-opsonized, noninvasive Salmonella mutants. Pretreating U937 cells with inhibitors of tyrosine kinases or phosphatidylinositol-3 kinase (PI-3K) completely blocked phagocytosis of opsonized Salmonella mutants but did not affect invasion by wild-type Salmonella or the apoptosis caused by invasion. However, pretreatment with GGTI-298, a geranylgeranyltransferase-1 inhibitor that prevents prenylation of Cdc42 and Rac1, suppressed Salmonella-induced apoptosis by ∼70%. Transduction of Tat fusion constructs containing dominant-negative Cdc42 or Rac1 significantly inhibited Salmonella-induced cell death, indicating that the cytotoxicity of Salmonella requires activation of Cdc42 and Rac. In contrast to phagocytosis of opsonized bacteria, invasion by S. typhimurium stimulated Cdc42 and Rac1, regardless of the activities of tyrosine- or PI-3K. Moreover, Salmonella infection activated Akt protein in a tyrosine-kinase or PI-3K-dependent manner, and a reduced expression of Akt by antisense transfection rendered the cells more sensitive to apoptosis induced by opsonized Salmonella. These results indicate that direct activation of Cdc42 and Rac1 by invasive Salmonella is a prerequisite of Salmonella-mediated death of U937 cells, whereas the simultaneous activation of Akt by tyrosine kinase and PI-3K during receptor-mediated phagocytosis protects cells from apoptosis.

Keywords
macrophages, bacterial apoptosis, signal transduction
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14003 (URN)10.1189/jlb.1202586 (DOI)
Available from: 2006-09-27 Created: 2006-09-27 Last updated: 2017-12-13Bibliographically approved
Tafazoli, F., Magnusson, K.-E. & Zheng, L. (2003). Disruption of Epithelial Barrier Integrity by Salmonella enterica Serovar Typhimurium Requires Geranylgeranylated Proteins. Infection and Immunity, 71(2), 872-881
Open this publication in new window or tab >>Disruption of Epithelial Barrier Integrity by Salmonella enterica Serovar Typhimurium Requires Geranylgeranylated Proteins
2003 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 71, no 2, p. 872-881Article in journal (Refereed) Published
Abstract [en]

Epithelial cells that line the human intestinal mucosa constitute the initial sites of host invasion by bacterial pathogens. A number of bacteria, such as Salmonella and Yersinia spp., have been shown to disrupt the integrity of the epithelial barrier, although little is known about the mechanisms underlying that effect. We found that polarized MDCK-1 epithelial cells infected with invasive Salmonella enterica serovar Typhimurium SL1344 exhibited marked changes in F-actin organization, an increase in the paracellular flux of dextran, and a rapid decrease in transepithelial electrical resistance (TER). In contrast, infection with an isogenic noninvasive mutant (hilA) increased the TER in these cells. Pretreating MDCK-1 cells with the inhibitors for tyrosine kinase (genistein) or phosphatidylinositol 3-kinase (wortmannin) did not affect invasion and subsequent perturbation of the epithelial barrier by serovar Typhimurium. Instead, the geranylgeranyltransferase 1 inhibitor GGTI-298, but not the farnesyltransferase inhibitor FTI-277, clearly reversed the capacity of serovar Typhimurium to disrupt the epithelial barrier. The substrates for GGTI-298 include Rho family GTPases, as indicated by inhibiting prenylation of Rac1 and Cdc42. Infection with wild-type serovar Typhimurium increased the level of activated Rac1 and Cdc42 and caused these proteins to accumulate apically in MDCK-1 cells. This Salmonella-induced accumulation of Rac1 and Cdc42 and alteration of the junction-associated proteins ZO-1, occludin, and E-cadherin in MDCK-1 cells were markedly inhibited by GGTI-298. These results suggest that activation of geranylgeranylated proteins, including Rac1 and Cdc42, is critical for disruption of barrier integrity by serovar Typhimurium in polarized MDCK-1 cells.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26543 (URN)10.1128/IAI.71.2.872-881.2003 (DOI)11105 (Local ID)11105 (Archive number)11105 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
Perskvist, N., Long, M., Stendahl, O. & Zheng, L. (2002). Mycobacterium tuberculosis Promotes Apoptosis in Human Neutrophils by Activating Caspase-3 and Altering Expression of Bax/Bcl-xL Via an Oxygen-Dependent Pathway. Journal of Immunology, 168(12), 6358-6365
Open this publication in new window or tab >>Mycobacterium tuberculosis Promotes Apoptosis in Human Neutrophils by Activating Caspase-3 and Altering Expression of Bax/Bcl-xL Via an Oxygen-Dependent Pathway
2002 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 168, no 12, p. 6358-6365Article in journal (Refereed) Published
Abstract [en]

In addition to direct bactericidal activities, such as phagocytosis and generation of reactive oxygen species (ROS), neutrophils can regulate the inflammatory response by undergoing apoptosis. We found that infection of human neutrophils with Mycobacterium tuberculosis (Mtb) induced rapid cell death displaying the characteristic features of apoptosis such as morphologic changes, phosphatidylserine exposure, and DNA fragmentation. Both a virulent (H37Rv) and an attenuated (H37Ra) strain of Mtb were equally effective in inducing apoptosis. Pretreatment of neutrophils with antioxidants or an inhibitor of NADPH oxidase markedly blocked Mtb-induced apoptosis but did not affect spontaneous apoptosis. Activation of caspase-3 was evident in neutrophils undergoing spontaneous apoptosis, but it was markedly augmented and accelerated during Mtb-induced apoptosis. The Mtb-induced apoptosis was associated with a speedy and transient increase in expression of Bax protein, a proapoptotic member of the Bcl-2 family, and a more prominent reduction in expression of the antiapoptotic protein Bcl-xL. Pretreatment with an inhibitor of NADPH oxidase distinctly suppressed the Mtb-stimulated activation of caspase-3 and alteration of Bax/Bcl-xL expression in neutrophils. These results indicate that infection with Mtb causes ROS-dependent alteration of Bax/Bcl-xL expression and activation of caspase-3, and thereby induces apoptosis in human neutrophils. Moreover, we found that phagocytosis of Mtb-induced apoptotic neutrophils markedly increased the production of proinflammatory cytokine TNF-α by human macrophages. Therefore, the ROS-dependent apoptosis in Mtb-stimulated neutrophils may represent an important host defense mechanism aimed at selective removal of infected cells at the inflamed site, which in turn aids the functional activities of local macrophages.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26523 (URN)11082 (Local ID)11082 (Archive number)11082 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
Alvarado-Kristensson, M., Pörn-Ares, M., Grethe, S., Smith, D., Zheng, L. & Andersson, T. (2002). p38 Mitogen-activated protein kinase and phosphatidylinositol 3-kinase activities have opposite effects on human neutrophil apoptosis.. The FASEB Journal, 16, 129-131
Open this publication in new window or tab >>p38 Mitogen-activated protein kinase and phosphatidylinositol 3-kinase activities have opposite effects on human neutrophil apoptosis.
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2002 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 16, p. 129-131Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26616 (URN)11181 (Local ID)11181 (Archive number)11181 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13
Blomgran, R., Stendalh, O. & Zheng, L. (2001). Activation of Protein Kinase B in human monocytic U937 cells by Salmonella typhimurium. Molecular Biology of the Cell, 12
Open this publication in new window or tab >>Activation of Protein Kinase B in human monocytic U937 cells by Salmonella typhimurium
2001 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 12, p. 1794-Conference paper, Published paper (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-49021 (URN)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12
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