Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

Pel, Melissa van; Os, Ronald van; Velders, Gerjo A.; Hagoort, Henny; Heegaard, Peter M. H.; Lindley, I. J. D.; Willemze, R.; Fibbe, Willem E.

doi:10.1073/pnas.0510192103

Cited by 55 publications

(56 citation statements)

References 39 publications

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“…Achieving effective therapeutic indices in such studies would benefit from the identification of specific biomarkers that might define the parameters that monitor either efficacy or toxicity. In this vein, accumulating evidence supports a role for serine protease inhibitor (serpins) family members in myeloproliferation and HPC mobilization (86,87). The down-regulation of serpins A1 and A3 during cell mobilization influences the marrow microenvironment and migratory behavior of HPCs.…”

Section: S-glutathionylationmentioning

confidence: 99%

Causes and Consequences of Cysteine S-Glutathionylation

Grek¹,

Zhang²,

Manevich³

et al. 2013

Journal of Biological Chemistry

282

275

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Post-translational S-glutathionylation occurs through the reversible addition of a proximal donor of glutathione to thiolate anions of cysteines in target proteins, where the modification alters molecular mass, charge, and structure/function and/or prevents degradation from sulfhydryl overoxidation or proteolysis. Catalysis of both the forward (glutathione S-transferase P) and reverse (glutaredoxin) reactions creates a functional cycle that can also regulate certain protein functional clusters, including those involved in redox-dependent cell signaling events. For translational application, S-glutathionylated serum proteins may be useful as biomarkers in individuals (who may also have polymorphic expression of glutathione S-transferase P) exposed to agents that cause oxidative or nitrosative stress.S-Glutathionylation targets cysteines in a basic environment (low pK a ) perhaps in close three-dimensional proximity to Arg, His, or Lys residues. Reports of reversible S-glutathionylation emerged as early as 1985 (1), but in concert with understanding the importance of reactive oxygen/nitrogen species (ROS/ RNS) 2 as second messengers, publications have increased substantially over the past 10 years. ROS/RNS signaling operates through a set of post-translational protein modifications that are discrete, site-specific, and reversible. Certain proteins undergo reversible chemical changes in response to altered localized redox potential. Among the most susceptible redoxsensitive targets are thiol (-SH) groups on cysteines. Signaling events are facilitated through redox-active proteins when one or more cysteines can exist as reactive thiolate anions. These cysteines are more nucleophilic and become susceptible to attack by GSH.Oxygen-based metabolism is arguably the most efficient and evolved method for producing energy from nutrients, but ROS

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Section: S-glutathionylationmentioning

confidence: 99%

Causes and Consequences of Cysteine S-Glutathionylation

Grek¹,

Zhang²,

Manevich³

et al. 2013

Journal of Biological Chemistry

282

275

View full text Add to dashboard Cite

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“…Radiotherapy may also increase the expression of protease inhibitors such as ␣1-antitrypsin that would diminish the protease storm during mobilization. 98 …”

Section: How I Treat Poor Hsc Mobilizers 4533mentioning

confidence: 99%

How I treat patients who mobilize hematopoietic stem cells poorly

Levesque

Herbert

2011

Blood

218

235

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Transplantation with 2-5 ؋ 10 6 mobilized CD34 ؉ cells/kg body weight lowers transplantation costs and mortality. Mobilization is most commonly performed with recombinant human G-CSF with or without chemotherapy, but a proportion of patients/donors fail to mobilize sufficient cells. BM disease, prior treatment, and age are factors influencing mobilization, but genetics also contributes. Mobilization may fail because of the changes affecting the HSC/progenitor cell/BM niche integrity and chemotaxis. Poor mobilization affects patient outcome and increases resource use. Until recently increasing G-CSF dose and adding SCF have been used in poor mobilizers with limited success. However, plerixafor through its rapid direct blockage of the CXCR4/CXCL12 chemotaxis pathway and synergy with G-CSF and chemotherapy has become a new and important agent for mobilization. Its efficacy in upfront and failed mobilizers is well established.To maximize HSC harvest in poor mobilizers the clinician needs to optimize current mobilization protocols and to integrate novel agents such as plerixafor. These include when to mobilize in relation to chemotherapy, how to schedule and perform apheresis, how to identify IntroductionHematopoietic stem cell transplantation (HSCT) has revolutionized the curative approach to a number of malignancies and BM failure syndromes by providing hematopoietic and immune rescue after high-dose cytoreductive therapy and, in allogeneic transplantations, graft-versus-tumor effect. [1][2][3][4] The term "mobilization" was first used to describe a 4-fold increase of circulating myeloid progenitors (granulocyte macrophage CFU [CFU-GM]) after the administration of endotoxin to healthy volunteers in 1977. 5 High levels of CFU-GM after recovery from myelosuppressive chemotherapy in humans was first described in 1976. 6 However, it was not until the 1980s that the use of chemotherapy-mobilized HSCs for transplantation was established. [7][8][9] Subsequently, a single high-dose cyclophosphamide was developed as a generic mobilizer. 10 Prof Metcalf led the study that showed the potential of G-CSF in mobilization. 11 Subsequently, 2 Australian centers in Melbourne and Adelaide showed for the first time the use of G-CSF-mobilized HSCs for transplantation, 12 and reports of combined G-CSF and chemotherapy mobilization soon followed. 13 Now, virtually all autologous and three-quarters of allogeneic transplantations are performed with mobilized HSCs (CIBMTR reports). 14,15 The cell dose effect of HSCT describes a threshold of HSCs that, when transplanted, is associated with rapid and sustained blood count recovery. 16 The benefits of rapid recovery are reduced hospitalization, blood product usage, and infections. 12,17 The minimum threshold for autologous transplantation is currently defined as 2 ϫ 10 6 CD34 ϩ cells/kg body weight (BW). 18 Many centers use a minimum of 3 ϫ 10 6 CD34 ϩ cells/kg BW for myeloablative and nonmyeloablative allogeneic and matched unrelated transplantations. Furthermore, Ͼ 5 ϫ 10 6 CD3...

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“…After G-CSF, the levels of serpin1 and serpin3 are reduced in the marrow, 82 thus making the marrow environment more proteolytic. In fact, administration of serpin1a inhibits interleukin (IL)-8-mediated mobilization, 83 although the role serpins play in G-CSF-mediated mobilization has yet to be defined.…”

Section: Neutrophil-derived Proteases Are Induced After G-csf Treatmentmentioning

confidence: 99%