Volume Articles

Immune Thrombocytopenia: Antiplatelet Autoantibodies Inhibit Proplatelet Formation by Megakaryocytes and Impair Platelet Production in vitro

José Perdomo

Haematology Research Unit, St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

Commentary: "Interference of Doxycycline Pretreatment in a Model of Abdominal Aortic Aneurysms"

Karina M. Mata¹*, Cleverson R. Fernandes¹, Cristiane Tefé-Silva², Simone G. Ramos¹

¹Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil

²University Center of Barão de Mauá, Ribeirão Preto, SP, Brazil

Abdominal aortic aneurysm (AAA) represents a complex pathophysiological process of weakening and dilatation of the aortic wall associated with atherosclerosis, chronic inflammatory response and hemodynamic alterations. Degradation of the extracellular matrix by the matrix metalloproteinases (MMPs) and an imbalance between MMPs and their tissue inhibitors (TIMPs), have fundamental roles in the development of AAA. However, the exact pathogenetic mechanisms remain incompletely elucidated. In addition to the previous results already published “Interference of doxycycline pretreatment in a model of abdominal aortic aneurysms”, in this commentary we have complementary results. Here we have included new findings of the TIMPs 1 and 2 expressions in animals submitted to AAA surgical induction associated with doxycycline pretreatment. In this study, we used a new experimental model, developed in our laboratory, to induce AAA by combining two potential causes of MMP secretion: inflammation and turbulent blood flow. Male Wistar rats were divided into Control (C), Control+ Doxycycline (C+D), Aneurysms (A) and Aneurysms+Doxycycline (A+D) groups. The rats were euthanized at 3, 7 or 15 days post-surgery (dps). The administrated doxycycline started 48 hours before the surgical induction of AAA until the end of the experiment. After 1, 3, 7, and 15 dps, the animals were euthanized under anesthesia and the vessels were collected to measurement of TIMPs 1 and 2 by western blot. Our results demonstrate an increased expression of TIMPs 1 and 2 in aneurysm group (A) probably in an attempt to counteract the increased activity of MMPs 2 and 9. In aneurysms groups submitted to doxycycline pretreatment (A+D) showed the regulation of expression of TIMP 1 and 2, remaining close to baseline levels from the third day, similar to expression found the control groups (C and C + D). This study suggests that the pretreatment with doxycycline balances the TIMPs 1 and 2 expressions with a protective effect on the progression of abdominal aortic aneurysms in experimental model.

Commentary on Paper "Drug-Induced HSP90 Inhibition Alleviates Pain in Monoarthritic Rats and Alters the Expression of New Putative Pain Players at the DRG"

Fani L. Moreira Neto^1,2,3*

¹Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal

²IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal

³Departamento de Biomedicina – Unidade de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Alameda Prof Hernâni Monteiro, 4200-319 Porto, Portugal

Heat shock protein 90 (HSP90) belongs to a highly conserved family of molecular chaperones and is responsible for regulating the protein folding quality control of specific client proteins. In a recent study published in Molecular Neurobiology, HSP90mRNA levels were found significantly decreased after knock-down in vitro of activating transcription factor 3 (ATF3), indicating that this stress-inducible gene that mediates pro-apoptosis or cytoprotection might act as positive regulator of HSP90 expression. In the rodent model of Monoarthritis, characterized by being accompanied by chronic joint inflammatory pain, the mRNA and protein levels for HSP90 were significantly increased in dorsal root ganglia (DRG). Additionally, a reversal in the HSP90 mRNA upregulation and in the 70kDa protein isoform levels following intrathecal delivery of a HSP90 inhibitor, along with an attenuation of movement-induced mechanical allodynia, and reduced neuronal sensitization and satellite glial cells (SGC) activation in ipsilateral DRG of the arthritic animals were also observed. This suggests a putative role of HSP90 in chronic inflammatory pain pathophysiology at sensory ganglia level that is still unexplored. To date only a few studies demonstrated a link between pain and HSP90 modulation, but there are several evidences that HSP90 is involved in inflammation, tumorigenesis and neurodegeneration. Here, we discuss the status of the studies demonstrating a role for HSP90 in inflammation and comment on their possible involvement in neuronal/glial driven pain mechanisms.

Emerging Evidence Supports the Hypothesis that Neutrophil Extracellular Traps are a Major Factor in Genesis and Progression of Chronic Obstructive Pulmonary Disease

Astrid Obermayer¹*, Walter Stoiber¹, Fikreta Grabcanovic-Musija², Michael Studnicka²

¹Department of Biosciences, Biomedical Ultrastructure Research, University of Salzburg, Salzburg, Austria

²University Clinic of Pneumology, Paracelsus Medical University, Salzburg, Austria

Since their discovery about fifteen years ago, neutrophil extracellular traps (NETs) have been recognized as an intrinsic part of vertebrate innate immunity and inflammatory response. Consisting of entangled strands of extracellular DNA decorated with histones, elastase, myeloperoxidase and other proteins, NETs entrap and kill pathogens, but are increasingly also found to contribute to acute and chronic inflammatory disease due to their toxicity to host cell and autoimmunity induction. Chronic obstructive pulmonary disease (COPD) turned out to be among the major disorders involving overshooting formation of NETs and associated adverse effect. In the present review, we summarize the progress in knowledge on the role of NETs in COPD pathology made since our first reports on this subject. We highlight recent substantial advances and discuss possible cause-and-effect relationships, connections with common comorbidities and interactions with drugs, also to illustrate the importance of NETs as a future diagnostic tool and target for new medication strategies.

A Review of a Diagnostic Tool: Galactomannan

Gulhadiye Avcu¹, Deniz Yilmaz Karapinar^2*

¹Ege University Faculty of Medicine, Children’s Hospital, Department of Pediatric Infectious Disease, 35040 Bornova Izmir, Turkey

²Ege University Faculty of Medicine, Children’s Hospital, Pediatric Hematology, 35040 Bornova Izmir, Turkey

Invasive fungal infections, including invasive aspergillosis are associated with a high morbidity and mortality especially in immunocompromised patients. Diagnosis is often difficult due to several factors such as delay in clinical suspicion and the lack of spesific clinical findings. Galactomannan is a polysaccharide cell wall component of Aspergillus and galactomannan antigen detection has become widely used for diagnosis of invasive aspergillosis. Here, we tried to discuss the diagnostic value of the galactomannan test in the context of literature review.

Expression, Functions, and Treatment Target of PD-L1 (B7-H1) in Multiple Myeloma

Hideto Tamura¹*, Mariko Ishibashi², Mika Sunakawa¹, Hidemi Takahashi², Koiti Inokuchi¹

¹Department of Hematology, Nippon Medical School, Tokyo, Japan

²Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan

Programmed death ligand 1 (PD-L1) expression on myeloma cells is induced by JAK2, STAT3, and MEK1/2-mediated interleukin-6 signaling, a strong inducer of PD-L1 interferon-γ produced by T and natural killer cells, and APRIL produced by osteoclasts in the tumor microenvironment. The soluble form of PD-L1, derived from extracellular domains of PD-L1 molecules expressed in the tumor environment, may also contribute to tumor immune evasion. PD-L1-expressing myeloma cells not only have the ability to escape from the attack of tumor-specific T cells but also high proliferation potential. Furthermore, PD-L1 on myeloma cells delivers a reverse signal to tumor cells through PD-1 binding, resulting in the phosphorylation of Akt accompanied by the acquisition of resistance to anti-myeloma agents. Based on the function of PD-L1 in myeloma, the blockade of the PD-1–PD-L1 pathway is a reasonable treatment in refractory patients. Phase I/II clinical trials of anti-PD-1 antibody combined with immunomodulatory drugs demonstrated excellent effects in heavily pretreated multiple myeloma patients with acceptable tolerability. The timing and combination drug of anti-PD-1/PD-L1 antibodies should be considered to improve clinical effects with low mortality in refractory myeloma patients.