scholarly journals 0993. Heme oxygenase - 1 attenuates acute pulmonary inflammation by decreasing the release of segmented neutrophils from the bone marrow

2014 ◽  
Vol 2 (S1) ◽  
Author(s):  
F Konrad ◽  
S Braun ◽  
I Vollmer ◽  
K-C Ngamsri ◽  
J Reutershan
Keyword(s):  
Bone Marrow ◽  
Heme Oxygenase ◽  
Pulmonary Inflammation ◽  
Heme Oxygenase 1

Heme oxygenase-1 attenuates acute pulmonary inflammation by decreasing the release of segmented neutrophils from the bone marrow

2014 ◽  
Vol 307 (9) ◽  
pp. L707-L717 ◽  
Author(s):  
Franziska M. Konrad ◽  
Stefan Braun ◽  
Kristian-Christos Ngamsri ◽  
Irene Vollmer ◽  
Jörg Reutershan
Keyword(s):  
Bone Marrow ◽  
Heme Oxygenase ◽  
Pulmonary Inflammation ◽  
Protoporphyrin Ix ◽  
Lavage Fluid ◽  
Polymorphonuclear Neutrophil ◽  
Heme Oxygenase 1 ◽  
Neutrophil Granulocytes ◽  
Show Evidence ◽  
Underlying Mechanisms

Recruiting polymorphonuclear neutrophil granulocytes (PMNs) from circulation and bone marrow to the site of inflammation is one of the pivotal mechanisms of the innate immune system. During inflammation, the enzyme heme oxygenase 1 (HO-1) has been shown to reduce PMN migration. Although these effects have been described in various models, underlying mechanisms remain elusive. Recent studies revealed an influence of HO-1 on different cells of the bone marrow. We investigated the particular role of the bone marrow in terms of HO-1-dependent pulmonary inflammation. In a murine model of LPS inhalation, stimulation of HO-1 by cobalt (III) protoporphyrin-IX-chloride (CoPP) resulted in reduced segmented PMN migration into the alveolar space. In the CoPP group, segmented PMNs were also decreased intravascularly, and concordantly, mature and immature PMN populations were higher in the bone marrow. Inhibition of the enzyme by tin protoporphyrin-IX increased segmented and banded PMN migration into the bronchoalveolar lavage fluid with enhanced PMN release from the bone marrow and aggravated parameters of tissue inflammation. Oxidative burst activity was significantly higher in immature compared with mature PMNs. The chemokine stromal-derived factor-1 (SDF-1), which mediates homing of leukocytes into the bone marrow and is decreased in inflammation, was increased by CoPP. When SDF-1 was blocked by the specific antagonist AMD3100, HO-1 activation was no longer effective in curbing PMN trafficking to the inflamed lungs. In conclusion, we show evidence that the anti-inflammatory effects of HO-1 are largely mediated by inhibiting the release of segmented PMNs from the bone marrow rather than direct effects within the lung.

scholarly journals Various roles of heme oxygenase-1 in response of bone marrow macrophages to RANKL and in the early stage of osteoclastogenesis

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Urszula Florczyk-Soluch ◽  
Ewelina Józefczuk ◽  
Jacek Stępniewski ◽  
Karolina Bukowska-Strakova ◽  
Mateusz Mendel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Heme Oxygenase ◽  
Early Stage ◽  
Heme Oxygenase 1

Transient Ex Vivo Inhibition of Heme Oxygenase 1 (HO-1) in Hematopoietic Stem/Progenitor Cells (HSPCs) By Small-Molecule Inhibitors Enhances Their Migratory Responsiveness to Bone Marrow (BM)-Secreted Chemoattractants a Novel and Simple Strategy to Improve Homing of HSPCs

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4272-4272
Author(s):  
Mateusz Adamiak ◽  
Joseph B Moore IV ◽  
John Zhao ◽  
Ahmed Abdelbaset-Ismail ◽  
Marcin Wysoczynski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Heme Oxygenase ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Negative Regulator ◽  
Heme Oxygenase 1 ◽  
Human Umbilical Cord ◽  
Hematopoietic Stem ◽  
Colony Forming Units

Abstract Background . Heme oxygenase 1 (HO-1) is an inducible stress-response enzyme that not only catalyzes the degradation of heme (e.g., released from erythrocytes) but also has an important function in various physiological and pathophysiological states associated with cellular stress, such as ischemic/reperfusion injury. HO-1 has a well-documented anti-inflammatory potential and inhibits complement cascade (ComC)-mediated inflammatory responses. Moreover, HO-1 has been reported to have a negative effect on adhesion and migration of neutrophils in acute inflammation in a model of peritonitis. Radiation chimeras created after transplantation with HSPCs having a mutation in one of the alleles of HO-1 engrafted much faster; however, a persistent decrease in HO-1 activity in these animals resulted in their enhanced sensitivity to stress and susceptibility to irradiation (Blood 2008, 112, 4494-4502). Moreover, we recently demonstrated that HO-1-deficient HSPCs show enhanced in vitro migration up an SDF-1 gradient (Stem Cell Rev & Rep. 2015, 11, 110-118). Hypothesis. Based on these findings, we hypothesized that transient inhibition of HO-1 by non-toxic, small-molecule inhibitors would enhance in vivo migration of HSPCs to bone marrow (BM)-derived chemoattractants and thus would facilitate their homing and accelerate hematopoietic recovery Materials and Methods . To address this issue, we first generated several human hematopoietic cell lines in which HO-1 was upregulated or downregulated. We also exposed murine and human BM-derived cells to small-molecule inhibitors or activators of HO-1 and performed dose and timing toxicity studies. Next, murine BM mononuclear cells (MNCs) and human umbilical cord blood (UCB) MNCs were exposed to the small-molecule HO-1 inhibitor Sn(IV) protoporphyrin IX dichloride (SnPP) and tested for their chemotactic response in Transwell migration assays to all currently known HSPC chemoattractants, including stromal-derived factor 1 (SDF-1), sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and the extracellular nucleotides ATP and UTP. For in vivo assays, lethally irradiated mice were transplanted with BM MNCs exposed or not exposed to SnPP, and in recipient animals we evaluated i) the number of day-12 colony-forming units in spleen (CFU-S) and colony-forming units for granulocyte/macrophage (CFU-GM) progenitors in BM and ii) the kinetics of peripheral blood (PB) count recovery by measuring the number of leucocytes, lymphocytes, and platelets. We also performed competitive repopulation studies with a limited number of transplanted BM MNCs using the CD45.1 and CD45.2 congenic mouse models. Results and Conclusions . We demonstrate here that HO-1 is a negative regulator of HSPC migration, and thus, by transiently inhibiting its activity in HSPCs with the non-toxic small-molecule inhibitor (SnPP), it is possible to accelerate homing and subsequent engraftment of HSPCs. We propose that this simple and inexpensive strategy could be employed in the clinical setting to improve seeding efficiency of transplanted HSPCs and their engraftment, particularly in those situations in which the number of HSPCs available for transplant is limited (e.g., from UCB or grafts harvested from poor mobilizers). Disclosures No relevant conflicts of interest to declare.

scholarly journals Heme Oxygenase-1 in Macrophages Impairs the Perfusion Recovery After Hindlimb Ischemia by Suppressing Autolysosome-Dependent Degradation of NLRP3

2021 ◽  
Author(s):  
Yuankun Ma ◽  
Liangliang Jia ◽  
Yidong Wang ◽  
Yongli Ji ◽  
Jian Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Blood Flow ◽  
Heme Oxygenase ◽  
Tissue Damage ◽  
Molecular Mechanisms ◽  
Capillary Density ◽  
Heme Oxygenase 1 ◽  
Inflammasome Activation ◽  
Hindlimb Ischemia ◽  
Antiangiogenic Effect

Objective: Macrophage-mediated inflammatory response is closely associated with the neovascularization process following hindlimb ischemia. We previously demonstrated that HO-1 (heme oxygenase-1) in macrophages evoked proinflammatory reactions and tissue damage. Here, we evaluated the role played by macrophage-derived HO-1 and elucidated its underlying molecular mechanisms in perfusion recovery after hindlimb ischemia. Approach and Results: We found significant upregulation of HO-1 in mouse ischemic muscles after hindlimb ischemia surgery and with most of this expression occurring in infiltrated macrophages. Myeloid conditional HO-1-deficient mice exhibited higher perfusion recovery, evidenced by restored blood flow, motor function and attenuated tissue damage as well as increased capillary density in the gastrocnemius muscles after hindlimb ischemia, relative to littermate controls. This protective effect was accompanied by reduced nod-like receptor family, NLRP3 (pyrin domain containing 3) inflammasome activation in the infiltrated macrophages without the alteration of macrophage infiltration and polarization. Moreover, suppressing inflammasome activation with NLRP3 inhibitor MCC950 improved blood flow and capillary density in wild-type mice compared with untreated mice. Mechanistically, suppressing HO-1 abolished TNF (tumor necrosis factor)-α-induced NLRP3 protein rather than mRNA expression in bone marrow–derived macrophages, indicating that HO-1 mediated post-transcriptional regulation of NLRP3. Furthermore, HO-1 inhibition promoted autolysosome-dependent degradation of NLRP3 in bone marrow–derived macrophages. Matrigel tube formation assay revealed that HO-1 deletion abrogated the antiangiogenic effect of inflammasome-activated macrophages. Conclusions: Taken together, these findings indicate that macrophage HO-1 deficiency promotes perfusion recovery after hindlimb ischemia by accelerating autolysosomal degradation of NLRP3. The underlying mechanism of action is a potential target for therapeutic angiogenesis in ischemic diseases.

scholarly journals Donor-Derived Myeloid Heme Oxygenase-1 Controls the Development of Graft-Versus-Host Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Chloé Spilleboudt ◽  
Virginie De Wilde ◽  
Philippe Lewalle ◽  
Ludovic Cabanne ◽  
Mathieu Leclerc ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Heme Oxygenase ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Heme Oxygenase 1 ◽  
Hematopoietic Stem ◽  
Graft Versus Host

Graft-versus-host disease (GVHD) remains a major clinical drawback of allogeneic hematopoietic stem cell transplantation (HSCT). Here, we investigated how the stress responsive heme catabolizing enzyme heme oxygenase-1 (HO-1, encoded by HMOX1) regulates GVHD in response to allogeneic hematopoietic stem cell transplantation in mice and humans. We found that deletion of the Hmox1 allele, specifically in the myeloid compartment of mouse donor bone marrow, promotes the development of aggressive GVHD after allogeneic transplantation. The mechanism driving GVHD in mice transplanted with allogeneic bone marrow lacking HO-1 expression in the myeloid compartment involves enhanced T cell alloreactivity. The clinical relevance of these observations was validated in two independent cohorts of HSCT patients. Individuals transplanted with hematopoietic stem cells from donors carrying a long homozygous (GT)n repeat polymorphism (L/L) in the HMOX1 promoter, which is associated with lower HO-1 expression, were at higher risk of developing severe acute GVHD as compared to donors carrying a short (GT)n repeat (S/L or S/S) polymorphism associated with higher HO-1 expression. In this study, we showed the unique importance of donor-derived myeloid HO-1 in the prevention of lethal experimental GVHD and we corroborated this observation by demonstrating the association between human HMOX1 (GT)n microsatellite polymorphisms and the incidence of severe acute GVHD in two independent HSCT patient cohorts. Donor-derived myeloid HO-1 constitutes a potential therapeutic target for HSCT patients and large-scale prospective studies in HSCT patients are necessary to validate the HO-1 L/L genotype as an independent risk factor for developing severe acute GVHD.

scholarly journals Vasculoprotective effects of heme oxygenase-1 in a murine model of hyperoxia-induced bronchopulmonary dysplasia

2012 ◽  
Vol 302 (8) ◽  
pp. L775-L784 ◽  
Author(s):  
Angeles Fernandez-Gonzalez ◽  
S. Alex Mitsialis ◽  
Xianlan Liu ◽  
Stella Kourembanas
Keyword(s):  
Bronchopulmonary Dysplasia ◽  
Heme Oxygenase ◽  
Ventricular Hypertrophy ◽  
Iron Homeostasis ◽  
Pulmonary Inflammation ◽  
Protective Role ◽  
Heme Oxygenase 1 ◽  
Protective Mechanisms ◽  
Vascular Growth ◽  
Anti Inflammatory

Bronchopulmonary dysplasia (BPD) is characterized by simplified alveolarization and arrested vascular development of the lung with associated evidence of endothelial dysfunction, inflammation, increased oxidative damage, and iron deposition. Heme oxygenase-1 (HO-1) has been reported to be protective in the pathogenesis of diseases of inflammatory and oxidative etiology. Because HO-1 is involved in the response to oxidative stress produced by hyperoxia and is critical for cellular heme and iron homeostasis, it could play a protective role in BPD. Therefore, we investigated the effect of HO-1 in hyperoxia-induced lung injury using a neonatal transgenic mouse model with constitutive lung-specific HO-1 overexpression. Hyperoxia triggered an increase in pulmonary inflammation, arterial remodeling, and right ventricular hypertrophy that was attenuated by HO-1 overexpression. In addition, hyperoxia led to pulmonary edema, hemosiderosis, and a decrease in blood vessel number, all of which were markedly improved in HO-1 overexpressing mice. The protective vascular response may be mediated at least in part by carbon monoxide, due to its anti-inflammatory, antiproliferative, and antiapoptotic properties. HO-1 overexpression, however, did not prevent alveolar simplification nor altered the levels of ferritin and lactoferrin, proteins involved in iron binding and transport. Thus the protective mechanisms elicited by HO-1 overexpression primarily preserve vascular growth and barrier function through iron-independent, antioxidant, and anti-inflammatory pathways.

Carbon Monoxide Therapy Modulates Hematopoietic Stem Cell Development in Heme-Oxygenase-1 Knockout Mice

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1318-1318
Author(s):  
Joan Denise Beckman ◽  
Paul H Marker ◽  
Julia Nguyen ◽  
John D Belcher ◽  
Anthony J. Croatt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Carbon Monoxide ◽  
Stem Cell ◽  
Heme Oxygenase ◽  
Blood Cells ◽  
Research Funding ◽  
S Phase ◽  
Cell Populations ◽  
Heme Oxygenase 1 ◽  
Cell Preservation

Abstract Abstract 1318 Previous studies have demonstrated that heme-oxygenase-1 (HO-1), the rate limiting enzyme in the catabolism of heme, is a regulator of the balance between hematopoiesis and stem cell preservation under stress. HO-1−/− mice display oxidative stress, anemia, and leukocytosis with chronic inflammation. We hypothesize that therapy with inhaled carbon monoxide (CO), a by-product of HO-1 activity with antioxidant and anti-apoptotic properties; will reduce stress hematopoiesis in HO-1−/− mice, reducing inflammation and redistributing hematopoietic potential. In order to test this hypothesis we treated 25 week old HO-1−/− mice and HO-1+/+ mice (n=7/strain) with 250 ppm inhaled CO for 1 h/day, 3 days/week for eight weeks and compared them to an equal number of untreated HO-1−/− and HO-1+/+ mice. After 8-weeks of treatment the mice were sacrificed and flow cytometry was performed on bone marrow to assess hematopoietic potential. Cell cycle analysis of the bone marrow demonstrates that untreated HO-1−/− mice have a significantly decreased percent of cells in S-phase compared to untreated HO-1+/+ mice. Treatment with CO significantly (p<0.05) increases the percent of cells in S-phase in HO-1−/− mice but not HO-1+/+ mice. Reactive oxygen species (ROS) production in lineage−, c-kit+, Sca-1+ (KLS) cell population was assessed using 5-(and 6-)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate dye. HO-1−/− mice have a significantly (p<0.001) increased proportion of ROS positive KLS cells compared with HO-1+/+ mice. Analysis of long-term (LT), short-term, and multipotent (MPP) progenitor cell populations was conducted. Treatment with CO significantly (p<0.05) increases the percent of LT-HSC and MPP progenitor cells in HO-1−/− mice but not HO-1+/+ mice. Concordantly, the total white blood cell count of the CO-treated mice increased significantly. The differential of the mature blood cells demonstrates significant shift in cell maturation, with significant increase in red blood cells, platelets, and lymphocytes and a significant decrease in monocytes. Combined this data indicates that CO therapy is able to modify the hematopoietic potential of HO-1−/− mice leading to a change in mature cell populations. We propose a model in which CO-mediated signaling initiates a homeostatic conditioning program in stem cells to balance hematopoiesis and stem cell preservation, ultimately leading to a change in the inflammatory milieu of the mice. Disclosures: Belcher: Sangart, Inc: Research Funding. Vercellotti:Sangart, Inc: Research Funding.

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