Publications by authors named "Leo E Otterbein"

129 Publications

Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity.

Cell Rep 2021 Apr;35(3):109018

Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Physical exercise has profound effects on quality of life and susceptibility to chronic disease; however, the regulation of skeletal muscle function at the molecular level after exercise remains unclear. We tested the hypothesis that the benefits of exercise on muscle function are linked partly to microtraumatic events that result in accumulation of circulating heme. Effective metabolism of heme is controlled by Heme Oxygenase-1 (HO-1, Hmox1), and we find that mouse skeletal muscle-specific HO-1 deletion (Tam-Cre-HSA-Hmox1) shifts the proportion of muscle fibers from type IIA to type IIB concomitant with a disruption in mitochondrial content and function. In addition to a significant impairment in running performance and response to exercise training, Tam-Cre-HSA-Hmox1 mice show remarkable muscle atrophy compared to Hmox1 controls. Collectively, these data define a role for heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise.
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http://dx.doi.org/10.1016/j.celrep.2021.109018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196422PMC
April 2021

Carbon Monoxide Suppresses Neointima Formation in Transplant Arteriosclerosis by Inhibiting Vascular Progenitor Cell Differentiation.

Arterioscler Thromb Vasc Biol 2021 Jun 15;41(6):1915-1927. Epub 2021 Apr 15.

Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (H.S., G.R.L., E.C., D.G., H.W., F.H.B., L.E.O.).

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.120.315558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159904PMC
June 2021

Carbon Monoxide: from Poison to Clinical Trials.

Trends Pharmacol Sci 2021 05 26;42(5):329-339. Epub 2021 Mar 26.

Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA. Electronic address:

Every cell has a highly sophisticated system for regulating heme levels, which is particularly important with regard to turnover. Heme degradation generates CO and while CO has long been viewed as a metabolic waste product, and at higher concentrations cellularly lethal, we now know that CO is an indispensable gasotransmitter that participates in fundamental physiological processes necessary for survival. Irrefutable preclinical data have resulted in concerted efforts to develop CO as a safe and effective therapeutic agent, but against this notion lies dogma that CO is a poison, especially to the brain. The emergence of this debate is discussed here highlighting the neuroprotective properties of CO through its role on the central circadian clock and ongoing strategies being developed for CO administration for clinical use.
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http://dx.doi.org/10.1016/j.tips.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134950PMC
May 2021

Direct Airway Instillation of Neutrophils Overcomes Chemotactic Deficits Induced by Injury.

Shock 2021 Jul;56(1):119-124

Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts.

Background: Trauma induces neutrophil migration toward injury sites, both initiating wound healing and protecting against local bacterial infection. We have previously shown that mitochondrial formyl peptides (mtFPs) released by injured tissues act as chemoattractants by ligating neutrophil (PMN) formyl peptide receptor 1 (FPR1). But this process can also internalize multiple neutrophil chemoattractant receptors and thus might limit neutrophil migration to the lung in response to bacteria. Our objective was to better understand susceptibility to pneumonia after injury and thus find ways to reverse it.

Methods And Results: We modeled the alveolar chemotactic environment in pulmonary infections by incubating Staphylococcus aureus or Escherichia coli with peripheral blood mononuclear cells. Survey of the chemotactic mediators in the resultant conditioned media (CM) showed multiple potent chemoattractants. Pretreating PMN with mtFPs to mimic injury potently reduced net migration toward CM and this net effect was mostly reversed by an FPR1 antagonist. Using an established mouse model of injury-dependent lung infection, we then showed simple instillation of exogenous unstimulated human neutrophils into the airway resulted in bacterial clearance from the lung.

Conclusion: Injury-derived mtFPs suppress global PMN localization into complex chemotactic environments like infected alveoli. Transplantation of naive exogenous human neutrophils into the airway circumvents that pathologic process and prevents development of post-traumatic pneumonia without injury noted to the recipients.
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http://dx.doi.org/10.1097/SHK.0000000000001691DOI Listing
July 2021

Monocyte exocytosis of mitochondrial danger-associated molecular patterns in sepsis suppresses neutrophil chemotaxis.

J Trauma Acute Care Surg 2021 01;90(1):46-53

From the Institute of Molecular Biomedicine (B.K., B.V.), Comenius University, Bratislava, Slovakia; Department of Surgery (J.P., W.H., H.I.K., M.B.Y., L.E.O., K.I., C.J.H.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachussets; Department of Emergency Medicine (W-.Y.K.), Seoul National University College of Medicine Seoul, Korea; College of Nursing (Q.Z.), Harbin Medical School, Daqing, China; and Departments of Biology and Biological Engineering (M.B.Y.), Massachusetts Institute of Technology, Boston, Massachussets.

Background: Trauma and sepsis both increase the risk for secondary infections. Injury mobilizes mitochondrial (MT) danger-associated molecular patterns (mtDAMPs) directly from cellular necrosis. It is unknown, however, whether sepsis can cause active MT release and whether mtDAMPs released by sepsis might affect innate immunity.

Methods: Mitochondrial release from human monocytes (Mo) was studied after LPS stimulation using electron microscopy and using fluorescent video-microscopy of adherent Mo using Mito-Tracker Green (MTG) dye. Release of MTG+ microparticles was studied using flow cytometry after bacterial stimulation by size exclusion chromatography of supernatants with polymerase chain reaction (PCR) for mitochondrial DNA (mtDNA). Human neutrophil (PMN), chemotaxis, and respiratory burst were studied after PMN incubation with mtDNA.

Results: LPS caused Mo to release mtDAMPs. Electron microscopy showed microparticles containing MT. mtDNA was present both in microvesicles and exosomes as shown by PCR of the relevant size exclusion chromatography bands. In functional studies, PMN incubation with mtDNA suppressed chemotaxis in a dose-dependent manner, which was reversed by chloroquine, suggesting an endosomal, toll-like receptor-9-dependent mechanism. In contrast, PMN respiratory burst was unaffected by mtDNA.

Conclusion: In addition to passive release of mtDAMPs by traumatic cellular disruption, inflammatory and infectious stimuli cause active mtDAMP release via microparticles. mtDNA thus released can have effects on PMN that may suppress antimicrobial function. mtDAMP-mediated "feed-forward" mechanisms may modulate immune responses and potentially be generalizable to other forms of inflammation. Where they cause immune dysfunction the effects can be mitigated if the pathways by which the mtDAMPs act are defined. In this case, the endosomal inhibitor chloroquine is benign and well tolerated. Thus, it may warrant study as a prophylactic antiinfective after injury or prior sepsis.
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http://dx.doi.org/10.1097/TA.0000000000002973DOI Listing
January 2021

Multiplexed Plasma Immune Mediator Signatures Can Differentiate Sepsis From NonInfective SIRS: American Surgical Association 2020 Annual Meeting Paper.

Ann Surg 2020 10;272(4):604-610

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

Objectives: Sepsis and sterile both release "danger signals' that induce the systemic inflammatory response syndrome (SIRS). So differentiating infection from SIRS can be challenging. Precision diagnostic assays could limit unnecessary antibiotic use, improving outcomes.

Methods: After surveying human leukocyte cytokine production responses to sterile damage-associated molecular patterns (DAMPs), bacterial pathogen-associated molecular patterns, and bacteria we created a multiplex assay for 31 cytokines. We then studied plasma from patients with bacteremia, septic shock, "severe sepsis," or trauma (ISS ≥15 with circulating DAMPs) as well as controls. Infections were adjudicated based on post-hospitalization review. Plasma was studied in infection and injury using univariate and multivariate means to determine how such multiplex assays could best distinguish infective from noninfective SIRS.

Results: Infected patients had high plasma interleukin (IL)-6, IL-1α, and triggering receptor expressed on myeloid cells-1 (TREM-1) compared to controls [false discovery rates (FDR) <0.01, <0.01, <0.0001]. Conversely, injury suppressed many mediators including MDC (FDR <0.0001), TREM-1 (FDR <0.001), IP-10 (FDR <0.01), MCP-3 (FDR <0.05), FLT3L (FDR <0.05), Tweak, (FDR <0.05), GRO-α (FDR <0.05), and ENA-78 (FDR <0.05). In univariate studies, analyte overlap between clinical groups prevented clinical relevance. Multivariate models discriminated injury and infection much better, with the 2-group random-forest model classifying 11/11 injury and 28/29 infection patients correctly in out-of-bag validation.

Conclusions: Circulating cytokines in traumatic SIRS differ markedly from those in health or sepsis. Variability limits the accuracy of single-mediator assays but machine learning based on multiplexed plasma assays revealed distinct patterns in sepsis- and injury-related SIRS. Defining biomarker release patterns that distinguish specific SIRS populations might allow decreased antibiotic use in those clinical situations. Large prospective studies are needed to validate and operationalize this approach.
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http://dx.doi.org/10.1097/SLA.0000000000004379DOI Listing
October 2020

Adaptive Potential of the Heme Oxygenase/Carbon Monoxide Pathway During Hypoxia.

Front Physiol 2020 22;11:886. Epub 2020 Jul 22.

Division of Pulmonary, Critical Care, and Sleep Medicine, University of California San Diego, School of Medicine, San Diego, CA, United States.

Heme oxygenase (HO) enzymes catalyze heme into biliverdin, releasing carbon monoxide (CO) and iron into circulation. These byproducts of heme degradation can have potent cytoprotective effects in the face of stressors such as hypoxia and ischemia-reperfusion events. The potential for exogenous use of CO as a therapeutic agent has received increasing attention throughout the past few decades. Further, HO and CO are noted as putatively adaptive in diving mammals and certain high-altitude human populations that are frequently exposed to hypoxia and/or ischemia-reperfusion events, suggesting that HO and endogenous CO afford an evolutionary advantage for hypoxia tolerance and are critical in cell survival and injury avoidance. Our goal is to describe the importance of examining HO and CO in several systems, the physiological links, and the genetic factors that underlie variation in the HO/CO pathway. Finally, we emphasize the ways in which evolutionary perspectives may enhance our understanding of the HO/CO pathway in the context of diverse clinical settings.
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http://dx.doi.org/10.3389/fphys.2020.00886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387684PMC
July 2020

Circulating Factors in Trauma Plasma Activate Specific Human Immune Cell Subsets.

Injury 2020 Apr 4;51(4):819-829. Epub 2020 Mar 4.

Brigham and Women's Hospital, 75 Francis St., Boston, MA, 02115, United States. Electronic address:

Background: Trauma causes tissue injury that results in the release of damage associated molecular patterns (DAMPs) and other mediators at the site of injury and systemically. Such mediators disrupt immune system homeostasis and may activate multicellular immune responses with downstream complications such as the development of infections and sepsis. To characterize these alterations, we used time-of-flight mass cytometry to determine how trauma plasma affects normal peripheral blood mononuclear cell (PBMC) activation to gain insights into the kinetics and nature of trauma-induced circulating factors on human immune cell populations. A better understanding of the components that activate cells in trauma may aid in the discovery of therapeutic targets.

Methods: PBMCs from healthy volunteers were cultured with 5% plasma (healthy, trauma-1day, or trauma-3day) or known DAMPs for 24 h. Samples were stained with a broad immunophenotyping CyTOF antibody panel. Multiplex (Luminex) cytokine assays were used to measure differences in multiple cytokine levels in healthy and trauma plasma samples.

Results: Plasma from day 1, but not day 3 trauma patients induced the acute expansion of CD11c+ NK cells and CD73+/CCR7+ CD8 T cell subpopulations. Additionally, trauma plasma did not induce CD4+ T cell expansion but did cause a phenotypic shift towards CD38+/CCR7+ expressing CD4+ T cells. Multiplex analysis of cytokines by Luminex showed increased levels of IL-1RA, IL-6 and IL-15 in trauma-1day plasma. Similar to trauma day 1 plasma, PBMC stimulation with known DAMPs showed activation and expansion of CD11c+ NK cells.

Conclusions: We hypothesized that circulating factors in trauma plasma would induce phenotypic activation of normal human immune cell subsets. Using an unbiased approach, we identified specific changes in immune cell subsets that respond to trauma plasma. Additionally, CD11c+ NK cells expanded in response to DAMPs and LPS, suggesting they may also be responding to similar components in trauma plasma. Collectively, our data demonstrate that the normal PBMC response to trauma plasma involves marked changes in specific subsets of NK and CD8+ T cell populations. Future studies will target the function of these trauma plasma reactive immune cell subsets. These findings have important implications for the field of acute traumatic injuries.
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http://dx.doi.org/10.1016/j.injury.2020.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441590PMC
April 2020

Formyl Peptide Receptor-1 Blockade Prevents Receptor Regulation by Mitochondrial Danger-Associated Molecular Patterns and Preserves Neutrophil Function After Trauma.

Crit Care Med 2020 02;48(2):e123-e132

Department of Surgery, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA.

Objectives: Trauma predisposes to systemic sterile inflammation (systemic inflammatory response syndrome) as well as infection, but the mechanisms linking injury to infection are poorly understood. Mitochondrial debris contains formyl peptides. These bind formyl peptide receptor-1, trafficking neutrophils to wounds, initiating systemic inflammatory response syndrome, and wound healing. Bacterial formyl peptides, however, also attract neutrophils via formyl peptide receptor-1. Thus, mitochondrial formyl peptides might suppress neutrophils antimicrobial function. Also, formyl peptide receptor-1 blockade used to mitigate systemic inflammatory response syndrome might predispose to sepsis. We examined how mitochondrial formyl peptides impact neutrophils functions contributing to antimicrobial responses and how formyl peptide receptor-1 antagonists affect those functions.

Design: Prospective study of human and murine neutrophils and clinical cohort analysis.

Setting: University research laboratory and level 1 trauma center.

Patients: Trauma patients, volunteer controls.

Animal Subjects: C57Bl/6, formyl peptide receptor-1, and formyl peptide receptor-2 knockout mice.

Interventions: Human and murine neutrophils functions were activated with autologous mitochondrial debris, mitochondrial formyl peptides, or bacterial formyl peptides followed by chemokines or leukotrienes. The experiments were repeated using formyl peptide receptor-1 antagonist cyclosporin H, "designer" human formyl peptide receptor-1 antagonists (POL7178 and POL7200), or anti-formyl peptide receptor-1 antibodies. Mouse injury/lung infection model was used to evaluate effect of formyl peptide receptor-1 inhibition.

Measurements And Main Results: Human neutrophils cytosolic calcium, chemotaxis, reactive oxygen species production, and phagocytosis were studied before and after exposure to mitochondrial debris, mitochondrial formyl peptides, and bacterial formyl peptides. Mitochondrial formyl peptide and bacterial formyl peptides had similar effects on neutrophils. Responses to chemokines and leukotrienes were suppressed by prior exposure to formyl peptides. POL7200 and POL7178 were specific antagonists of human formyl peptide receptor-1 and more effective than cyclosporin H or anti-formyl peptide receptor-1 antibodies. Formyl peptides inhibited mouse neutrophils responses to chemokines only if formyl peptide receptor-1 was present. Formyl peptide receptor-1 blockade did not inhibit neutrophils bacterial phagocytosis or reactive oxygen species production. Cyclosporin H increased bacterial clearance in lungs after injury.

Conclusions: Formyl peptides both activate and desensitize neutrophils. Formyl peptide receptor-1 blockade prevents desensitization, potentially both diminishing systemic inflammatory response syndrome and protecting the host against secondary infection after tissue trauma or primary infection.
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http://dx.doi.org/10.1097/CCM.0000000000004094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337247PMC
February 2020

Carbon monoxide: An emerging therapy for acute kidney injury.

Med Res Rev 2020 07 9;40(4):1147-1177. Epub 2019 Dec 9.

Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia.

Treating acute kidney injury (AKI) represents an important unmet medical need both in terms of the seriousness of this medical problem and the number of patients. There is also a large untapped market opportunity in treating AKI. Over the years, there has been much effort in search of therapeutics with minimal success. However, over the same time period, new understanding of the underlying pathobiology and molecular mechanisms of kidney injury have undoubtedly helped the search for new therapeutics. Along this line, carbon monoxide (CO) has emerged as a promising therapeutic agent because of its demonstrated cytoprotective, and immunomodulatory effects. CO has also been shown to sensitize cancer, but not normal cells, to chemotherapy. This is particularly important in treating cisplatin-induced AKI, a common clinical problem that develops in patients receiving cisplatin therapies for a number of different solid organ malignancies. This review will examine and make the case that CO be developed into a therapeutic agent against AKI.
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http://dx.doi.org/10.1002/med.21650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280078PMC
July 2020

Endotoxin Engages Mitochondrial Quality Control an iNOS-Reactive Oxygen Species Signaling Pathway in Hepatocytes.

Oxid Med Cell Longev 2019 24;2019:4745067. Epub 2019 Oct 24.

Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: Organ injury and dysfunction in sepsis accounts for significant morbidity and mortality. Adaptive cellular responses in the setting of sepsis prevent injury and allow for organ recovery. We and others have shown that part of the adaptive response includes regulation of cellular respiration and maintenance of a healthy mitochondrial population. Herein, we hypothesized that endotoxin-induced changes in hepatocyte mitochondrial respiration and homeostasis are regulated by an inducible nitric oxide synthase/nitric oxide (iNOS/NO)-mitochondrial reactive oxygen species (mtROS) signaling axis, involving activation of the NRF2 signaling pathway.

Methods: Wild-type (C57Bl/6) or iNos male mice were subjected to intraperitoneal lipopolysaccharide (LPS) injections to simulate endotoxemia. Individual mice were randomized to treatment with NO-releasing agent DPTA-NONOate, mtROS scavenger MitoTEMPO, or vehicle controls. Other mice were treated with scramble or -specific siRNA tail vein injection. Primary murine hepatocytes were utilized for studies with or without LPS stimulation. Oxygen consumption rates were measured to establish mitochondrial respiratory parameters. Western blotting, confocal microscopy with immunocytochemistry, and rtPCR were performed for analysis of iNOS as well as markers of both autophagy and mitochondrial biogenesis.

Results: LPS treatment inhibited aerobic respiration in wild-type but not cells. Experimental endotoxemia or induced iNOS protein and mtROS production. However, induction of mtROS was dependent on iNOS expression. Furthermore, LPS-induced hepatic autophagy/mitophagy and mitochondrial biogenesis were significantly attenuated in mice or cells with NO or mtROS scavenging. These responses were rescued in mice delivery of NO both and . These data suggest that regulation of mitochondrial quality control following hepatocyte LPS exposure is dependent at least in part on a NO-mtROS signaling network. Further investigation to identify specific agents that modulate this process may facilitate the prevention of organ injury in sepsis.
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http://dx.doi.org/10.1155/2019/4745067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854992PMC
April 2020

Conquering Radicals with a Sense of Humor.

Authors:
Leo E Otterbein

Cell Chem Biol 2019 10;26(10):1335-1337

Harvard Medical School, Beth Israel Deaconess Medical Center, Department of Surgery, Boston, MA 02215, USA. Electronic address:

In this issue of Cell Chemical Biology, Vasavda et al. (2019) present data supporting a neuroprotective role for bilirubin, a bioactive product resulting from heme degradation. While the antioxidant capability of bilirubin is well documented, its role in modulating superoxide radical signaling offers new insight into the regulation of neurotransmission and neuronal survival.
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http://dx.doi.org/10.1016/j.chembiol.2019.10.001DOI Listing
October 2019

HO-1 and CD39: It Takes Two to Protect the Realm.

Front Immunol 2019 26;10:1765. Epub 2019 Jul 26.

Departments of Surgery and Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.

Cellular protective mechanisms exist to ensure survival of the cells and are a fundamental feature of all cells that is necessary for adapting to changes in the environment. Indeed, evolution has ensured that each cell is equipped with multiple overlapping families of genes that safeguard against pathogens, injury, stress, and dysfunctional metabolic processes. Two of the better-known enzymatic systems, conserved through all species, include the heme oxygenases (HO-1/HO-2), and the ectonucleotidases (CD39/73). Each of these systems generates critical bioactive products that regulate the cellular response to a stressor. Absence of these molecules results in the cell being extremely predisposed to collapse and, in most cases, results in the death of the cell. Recent reports have begun to link these two metabolic pathways, and what were once exclusively stand-alone are now being found to be intimately interrelated and do so through their innate ability to generate bioactive products including adenosine, carbon monoxide, and bilirubin. These simple small molecules elicit profound cellular physiologic responses that impact a number of innate immune responses, and participate in the regulation of inflammation and tissue repair. Collectively these enzymes are linked not only because of the mitochondria being the source of their substrates, but perhaps more importantly, because of the impact of their products on specific cellular responses. This review will provide a synopsis of the current state of the field regarding how these systems are linked and how they are now being leveraged as therapeutic modalities in the clinic.
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http://dx.doi.org/10.3389/fimmu.2019.01765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676250PMC
October 2020

Caveolin-1 selectively regulates microRNA sorting into microvesicles after noxious stimuli.

J Exp Med 2019 09 24;216(9):2202-2220. Epub 2019 Jun 24.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University Medical Campus, Boston, MA

Emerging evidence suggests that extracellular vesicle (EV)-containing miRNAs mediate intercellular communications in response to noxious stimuli. It remains unclear how a cell selectively sorts the cellular miRNAs into EVs. We report that caveolin-1 (cav-1) is essential for sorting of selected miRNAs into microvesicles (MVs), a main type of EVs generated by outward budding of the plasma membrane. We found that cav-1 tyrosine 14 (Y14)-phosphorylation leads to interactions between cav-1 and hnRNPA2B1, an RNA-binding protein. The cav-1/hnRNPA2B1 complex subsequently traffics together into MVs. Oxidative stress induces -GlcNAcylation of hnRNPA2B1, resulting in a robustly altered hnRNPA2B1-bound miRNA repertoire. Notably, cav-1 pY14 also promotes hnRNPA2B1 -GlcNAcylation. Functionally, macrophages serve as the principal recipient of epithelial MVs in the lung. MV-containing cav-1/hnRNPA2B1 complex-bound miR-17/93 activate tissue macrophages. Collectively, cav-1 is the first identified membranous protein that directly guides RNA-binding protein into EVs. Our work delineates a novel mechanism by which oxidative stress compels epithelial cells to package and secrete specific miRNAs and elicits an innate immune response.
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http://dx.doi.org/10.1084/jem.20182313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719430PMC
September 2019

Deletion of Biliverdin Reductase A in Myeloid Cells Promotes Chemokine Expression and Chemotaxis in Part via a Complement C5a--C5aR1 Pathway.

J Immunol 2019 05 5;202(10):2982-2990. Epub 2019 Apr 5.

Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

Biliverdin reductase (BVR)-A is a pleotropic enzyme converting biliverdin to bilirubin and a signaling molecule that has cytoprotective and immunomodulatory effects. We recently showed that biliverdin inhibits the expression of complement activation fragment 5a receptor one (C5aR1) in RAW 264.7 macrophages. In this study, we investigated the role of BVR-A in determining macrophage inflammatory phenotype and function via regulation of C5aR1. We assessed expression of C5aR1, M1-like macrophage markers, including chemokines (RANTES, IP-10), as well as chemotaxis in response to LPS and C5a in bone marrow-derived macrophages from and mice (conditional deletion of BVR-A in myeloid cells). In response to LPS, macrophages isolated from showed significantly elevated levels of C5aR1 as well as chemokines (RANTES, IP10) but not proinflammatory markers, such as iNOS and TNF. An increase in C5aR1 expression was also observed in peritoneal macrophages and several tissues from mice in a model of endotoxemia. In addition, knockdown of BVR-A resulted in enhanced macrophage chemotaxis toward C5a. Part of the effects of BVR-A deletion on chemotaxis and RANTES expression were blocked in the presence of a C5aR1 neutralizing Ab, confirming the role of C5a-C5aR1 signaling in mediating the effects of BVR. In summary, BVR-A plays an important role in regulating macrophage chemotaxis in response to C5a via modulation of C5aR1 expression. In addition, macrophages lacking BVR-A are characterized by the expression of M1 polarization-associated chemokines, the levels of which depend in part on C5aR1 signaling.
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http://dx.doi.org/10.4049/jimmunol.1701443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504595PMC
May 2019

Oral carbon monoxide therapy in murine sickle cell disease: Beneficial effects on vaso-occlusion, inflammation and anemia.

PLoS One 2018 11;13(10):e0205194. Epub 2018 Oct 11.

University of Minnesota, Department of Medicine, Vascular Research Center, Division of Hematology, Oncology and Transplantation, Minneapolis, MN, United States of America.

Carbon monoxide (CO) at low, non-toxic concentrations has been previously demonstrated to exert anti-inflammatory protection in murine models of sickle cell disease (SCD). However CO delivery by inhalation, CO-hemoglobin infusion or CO-releasing molecules presents problems for daily CO administration. Oral administration of a CO-saturated liquid avoids many of these issues and potentially provides a platform for self-administration to SCD patients. To test if orally-delivered CO could modulate SCD vaso-occlusion and inflammation, a liquid CO formulation (HBI-002) was administered by gavage (10 ml/kg) once-daily to NY1DD and Townes-SS transgenic mouse models of SCD. Baseline CO-hemoglobin (CO-Hb) levels were 1.6% and 1.8% in NY1DD and Townes-SS sickle mice and 0.6% in Townes-AS control mice. CO-Hb levels reached 5.4%, 4.7% and 3.0% within 5 minutes in NY1DD, SS and AS mice respectively after gavage with HBI-002. After ten treatments, each once-daily, hemoglobin levels rose from 5.3g/dL in vehicle-treated Townes-SS mice to 6.3g/dL in HBI-002-treated. Similarly, red blood cell (RBC) counts rose from 2.36 x 106/μL in vehicle-treated SS mice to 2.89 x 106/μL in HBI-002-treated mice. In concordance with these findings, hematocrits rose from 26.3% in vehicle-treated mice to 30.0% in HBI-002-treated mice. Reticulocyte counts were not significantly different between vehicle and HBI-002-treated SS mice implying less hemolysis and not an increase in RBC production. White blood cell counts decreased from 29.1 x 103/μL in vehicle-treated versus 20.3 x 103/μL in HBI-002-treated SS mice. Townes-SS mice treated with HBI-002 had markedly increased Nrf2 and HO-1 expression and decreased NF-κB activation compared to vehicle-treated mice. These anti-inflammatory effects were examined for the ability of HBI-002 (administered orally once-daily for up to 5 days) to inhibit vaso-occlusion induced by hypoxia-reoxygenation. In NY1DD and Townes-SS sickle mice, HBI-002 decreased microvascular stasis in a duration-dependent manner. Collectively, these findings support HBI-002 as a useful anti-inflammatory agent to treat SCD and warrants further development as a therapeutic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205194PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181332PMC
March 2019

HIF-1α-induced xenobiotic transporters promote Th17 responses in Crohn's disease.

J Autoimmun 2018 11 8;94:122-133. Epub 2018 Aug 8.

Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, 02215, Boston, USA. Electronic address:

In Crohn's disease, pathogenic Th17-cells express low levels of CD39 ectonucleotidase and are refractory to the immunosuppressive effects of unconjugated bilirubin (UCB), an endogenous ligand for aryl-hydrocarbon-receptor (AhR). This resistance to AhR ligation might be associated with alterations in responses to hypoxia. Limited exposure to hypoxia appears beneficial in acute tissue injury. However, in protracted inflammation, hypoxemia may paradoxically result in Th17-cell activation. We report here that in vitro exposure of Th17-cells from Crohn's disease patients to hypoxia limits responsiveness to AhR stimulation by UCB, as reflected by lower CD39 levels. Blockade of hypoxia-inducible-factor-1alpha (HIF-1α) upregulates CD39 and favors Th17-cell regulatory responses. Resistance of Th17-cells to AhR signaling results, in part, from HIF-1α-dependent induction of ATP-binding cassette (ABC) transporters: multidrug-resistance-protein-1 (MDR1) and multidrug-resistance-associated-protein-4 (MRP4). Increased ABC transporters promote efflux of suppressive AhR ligands, such as UCB, from Th17-cells. Inhibition of MDR1, MRP4 and/or HIF-1α with ritonavir (RTV) reconstitutes AhR function in Th17-cells, enhancing therapeutic effects of UCB in dextran-sulfate-sodium-induced experimental colitis. Deleterious effects of hypoxia on Th17-cells in Crohn's disease can be ameliorated either by inhibiting HIF-1α or by suppressing ABC transporters to increase UCB availability as an AhR substrate. Targeting HIF-1α-ABC transporters could provide innovative therapeutic pathways for IBD.
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http://dx.doi.org/10.1016/j.jaut.2018.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193817PMC
November 2018

Where is the Clinical Breakthrough of Heme Oxygenase-1 / Carbon Monoxide Therapeutics?

Curr Pharm Des 2018 ;24(20):2264-2282

Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Center for Life Sciences, Harvard Medical School, Boston, MA 02215, United States.

Heme oxygenase (HO), the rate-limiting step in the degradation of heme to biliverdin, ferrous ion, and carbon monoxide (CO), is an ancestral protective enzyme conserved across phylogenetic domains. While HO was first described in the late 1960s and progressively characterized in the following decades, there has been a surge of innovation over the past twenty years in efforts to leverage the cytoprotective power of HO in a clinical setting. Despite the plethora of preclinical data indicating extraordinary therapeutic potential, HO has remained elusive from the physician's toolbox. The leading candidate in development, CO, has long been misconstrued as a useless toxic gas. Scientists have crafted an array of CO delivery molecules and devices to harness HO, however, each endeavor was met with limitations preventing translation into clinical practice. In this discussion, we summarize the HO / CO field with a clinical and commercial development perspective. More specifically, given the enormous global efforts and capital investment into the field, we ask: where is the breakthrough therapy?
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http://dx.doi.org/10.2174/1381612824666180723161811DOI Listing
October 2019

A subset of five human mitochondrial formyl peptides mimics bacterial peptides and functionally deactivates human neutrophils.

J Trauma Acute Care Surg 2018 11;85(5):936-943

From the Department of Surgery and Center for Vascular Biology Research (E.K.), Department of Surgery (C.J.H., L.C., N.S., L.E.O., C.H.C., K.I.), Department of Surgery, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts; Department of Emergency Medicine (W.Y.K.), Seoul National University College of Medicine, Seoul, Republic of Korea; Massachusetts Institute of Technology (I.R., M.B.Y.), Cambridge, Massachusetts; and mAbDx, Inc (Y.C., M.M.), Eugene, Oregon.

Background: Trauma causes inflammation by releasing mitochondria that act as Danger-Associated Molecular Patterns (DAMPs). Trauma also increases susceptibility to infection. Human mitochondria contain 13 N-formyl peptides (mtFPs). We studied whether mtFPs released into plasma by clinical injury induce neutrophil (PMN) inflammatory responses, whether their potency reflects their similarity to bacterial FPs and how their presence at clinically relevant concentration affects PMN function.

Methods: N-terminal sequences of the 13 mtFPs were synthesized. Changes in human PMN cytosolic Ca concentration ([Ca]i) and chemotactic responses to mtFPs were studied. Sequence similarity of mtFPs to the canonical bacterial peptide f-Met-Leu-Phe (fMLF/fMLP) was studied using the BLOcks SUbstitution Matrix 62 (BLOSUM 62) system. The presence of mtFPs in plasma of trauma patients was assayed by Enzyme-linked immunosorbent assay (ELISA). The effects of the most potent mtFP (ND6) on PMN signaling and function were then studied at ambient clinical concentrations by serial exposure of native PMN to ND6, chemokines and leukotrienes.

Results: Five mtFPs (ND6, ND3, ND4, ND5, and Cox 1) induced [Ca]i flux and chemotaxis in descending order of potency. Evolutionary similarity to fMLF predicted [Ca]i flux and chemotactic potency linearly (R = 0.97, R = 0.95). Chemoattractant potency was also linearly related to [Ca]i flux induction (R = 0.92). Active mtFPs appear to circulate in significant amounts immediately after trauma and persist through the first week. The most active mtFP, ND6, suppresses responses to physiologic alveolar chemoattractants (CXCL-1, leukotriene B4) as well as to fMLF where CXCL-1 and leukotriene B4 do not suppress N-formyl peptide receptor (FPR)-1 responses to mtFPs. Prior FPR-1 inhibition rescues PMN from heterologous suppression of CXCR-1 and BLT-1 by mtFPs.

Conclusion: The data suggest mtFPs released by injured tissue may attract PMN to trauma sites while suppressing PMN responses to other chemoattractants. Inhibition of mtFP-FPR1 interactions might increase PMN recruitment to lung bacterial inoculation after trauma. These findings suggest new paradigms for preventing infections after trauma.

Level Of Evidence: Therapeutic, Level IV.
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http://dx.doi.org/10.1097/TA.0000000000001971DOI Listing
November 2018

Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide.

Nat Chem 2018 07 14;10(7):787-794. Epub 2018 May 14.

Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA.

Controlled activation is a critical component in prodrug development. Here we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two 'click and release' systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of the approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix following the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biological and therapeutic effects in vitro and in vivo when compared to controls, which did not result in enrichment. This method is thus a platform for targeted drug delivery that is amenable to conjugation with a variety of molecules and is not limited to cell-surface delivery. Taken together, these two 'click and release' pairs clearly demonstrate the concept of enrichment-triggered drug release and the critical feasibility of treating clinically relevant diseases such as acute liver injury and cancer.
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http://dx.doi.org/10.1038/s41557-018-0055-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235738PMC
July 2018

Carbon monoxide protects the kidney through the central circadian clock and CD39.

Proc Natl Acad Sci U S A 2018 03 20;115(10):E2302-E2310. Epub 2018 Feb 20.

Transplant Institute, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

Ischemia reperfusion injury (IRI) is the predominant tissue insult associated with organ transplantation. Treatment with carbon monoxide (CO) modulates the innate immune response associated with IRI and accelerates tissue recovery. The mechanism has been primarily descriptive and ascribed to the ability of CO to influence inflammation, cell death, and repair. In a model of bilateral kidney IRI in mice, we elucidate an intricate relationship between CO and purinergic signaling involving increased CD39 ectonucleotidase expression, decreased expression of Adora1, with concomitant increased expression of Adora2a/2b. This response is linked to a >20-fold increase in expression of the circadian rhythm protein Period 2 (Per2) and a fivefold increase in serum erythropoietin (EPO), both of which contribute to abrogation of kidney IRI. CO is ineffective against IRI in and mice or in the presence of a neutralizing antibody to EPO. Collectively, these data elucidate a cellular signaling mechanism whereby CO modulates purinergic responses and circadian rhythm to protect against injury. Moreover, these effects involve CD39- and adenosinergic-dependent stabilization of Per2. As CO also increases serum EPO levels in human volunteers, these findings continue to support therapeutic use of CO to treat IRI in association with organ transplantation, stroke, and myocardial infarction.
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http://dx.doi.org/10.1073/pnas.1716747115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877926PMC
March 2018

Intraoperative oxygen concentration and neurocognition after cardiac surgery: study protocol for a randomized controlled trial.

Trials 2017 Dec 19;18(1):600. Epub 2017 Dec 19.

Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA, 02215, USA.

Background: Postoperative cognitive dysfunction (POCD) is a common complication of cardiac surgery. Studies have identified potentially injurious roles for cardiopulmonary bypass (CPB) and subsequent reperfusion injury. Cognitive dysfunction has also been linked to the deleterious effects of hyperoxia following ischemia-reperfusion injuries in several disease states, but there has been surprisingly little study into the role of hyperoxia in reperfusion injury after CPB. The potential for tightly regulated intraoperative normoxia to ameliorate the neurocognitive decline following cardiac surgery has not been investigated in a prospective manner. We hypothesize that the use of a protocolized management strategy aimed towards maintenance of an intraoperative normoxic level of oxygen, as opposed to hyperoxia, will reduce the incidence of POCD in older patients undergoing cardiac surgery.

Methods/design: One hundred patients aged 65 years and older undergoing non-emergency coronary artery bypass grafting surgery on cardiopulmonary bypass will be enrolled in this prospective, randomized, controlled trial. Subjects will be randomized to receive a fraction of inspired oxygen of either 35% or 100% while under general anesthesia throughout the intraoperative period. The primary outcome measure will be the incidence of POCD in the acute postoperative phase and up to 6 months. The assessment of neurocognition will be undertaken by trained personnel, blinded to study group, with the telephone Montreal Cognitive Assessment (t-MoCA) tool. Secondary outcome measures will include assessment of delirium using the Confusion Assessment Method (CAM and CAM-ICU), as well as time to extubation, days of mechanical ventilation, length of ICU and hospital stay and mortality at 6 months. With the aim of later identifying mechanistic aspects of the effect of oxygen tension, blood, urine, and atrial tissue specimens will be taken at various time points during the perioperative period and later analyzed.

Discussion: This trial will be one of the first randomized controlled studies to prospectively assess the relationship between intraoperative oxygen levels and postoperative neurocognition in cardiac surgery. It addresses a promising biological avenue of intervention in this vulnerable aging population.

Trial Registration: ClinicalTrials.gov Identifier: NCT02591589 , registered February 13, 2015.
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http://dx.doi.org/10.1186/s13063-017-2337-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735533PMC
December 2017

Clinical Implications of Hyperoxia.

Int Anesthesiol Clin 2018 ;56(1):68-79

Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

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http://dx.doi.org/10.1097/AIA.0000000000000176DOI Listing
March 2019

Carbon Monoxide Preserves Circadian Rhythm to Reduce the Severity of Subarachnoid Hemorrhage in Mice.

Stroke 2017 09 26;48(9):2565-2573. Epub 2017 Jul 26.

From the Department of Surgery (N.S., J.-L.L., D.G., L.E.O.) and Department of Neurology (R.H.L., P.M.F., K.A.H.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Department of Anesthesiology and Critical Care, Medical Center-University Freiburg, Faculty of Medicine, Germany (N.S., J.-L.L.); and Aston University, Birmingham, United Kingdom (L.E.O.).

Background And Purpose: Subarachnoid hemorrhage (SAH) is associated with a temporal pattern of stroke incidence. We hypothesized that natural oscillations in gene expression controlling circadian rhythm affect the severity of neuronal injury. We moreover predict that heme oxygenase-1 (HO-1/) and its product carbon monoxide (CO) contribute to the restoration of rhythm and neuroprotection.

Methods: Murine SAH model was used where blood was injected at various time points of the circadian cycle. Readouts included circadian clock gene expression, locomotor activity, vasospasm, neuroinflammatory markers, and apoptosis. In addition, cerebrospinal fluid and peripheral blood leukocytes from SAH patients and controls were analyzed for clock gene expression.

Results: Significant elevations in the clock genes , , and were observed in the hippocampus, cortex, and suprachiasmatic nucleus in mice subjected to SAH at zeitgeber time (ZT) 12 when compared with ZT2. Clock gene expression amplitude correlated with basal expression of HO-1, which was also significantly greater at ZT12. SAH animals showed a significant reduction in cerebral vasospasm, neuronal apoptosis, and microglial activation at ZT12 compared with ZT2. In animals with myeloid-specific HO-1 deletion ( ), , and expression was reduced in the suprachiasmatic nucleus, which correlated with increased injury. Treatment with low-dose CO rescued mice, restored , expression, and reduced neuronal apoptosis.

Conclusions: Clock gene expression regulates, in part, the severity of SAH and requires myeloid HO-1 activity to clear the erythrocyte burden and inhibit neuronal apoptosis. Exposure to CO rescues the loss of HO-1 and thus merits further investigation in patients with SAH.
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http://dx.doi.org/10.1161/STROKEAHA.116.016165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575974PMC
September 2017

Lung Epithelial Cell-Derived Microvesicles Regulate Macrophage Migration via MicroRNA-17/221-Induced Integrin β Recycling.

J Immunol 2017 08 3;199(4):1453-1464. Epub 2017 Jul 3.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University, Boston, MA 02118; and

Robust lung inflammation is one of the prominent features in the pathogenesis of acute lung injury (ALI). Macrophage migration and recruitment are often seen at the early stage of lung inflammatory responses to noxious stimuli. Using an acid inhalation-induced lung injury model, we explored the mechanisms by which acid exposure initiates macrophage recruitment and migration during development of ALI. The lung epithelium comprises a large surface area and functions as a first-line defense against noxious insults. We found that acid exposure induced a remarkable microvesicle (MV) release from lung epithelium as detected in bronchoalveolar lavage fluid. Significantly elevated RNA, rather than protein, was found in these epithelium-derived MVs after acid and included several highly elevated microRNAs, including microRNA (miR)-17 and miR-221. Acid-induced epithelial MV release promoted macrophage migration in vitro and recruitment into the lung in vivo and required, in part, MV shuttling of miR-17 and/or miR-221. Mechanistically, acid-induced epithelial MV miR-17/221 promoted β integrin recycling and presentation back onto the surface of macrophages, in part via a Rab11-mediated pathway. Integrin β is known to play an essential role in regulating macrophage migration. Taken together, acid-induced ALI results in epithelial MV shuttling of miR-17/221 that in turn modulates macrophage β integrin recycling, promoting macrophage recruitment and ultimately contributing to lung inflammation.
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http://dx.doi.org/10.4049/jimmunol.1700165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561736PMC
August 2017

Intratracheal instillation of neutrophils rescues bacterial overgrowth initiated by trauma damage-associated molecular patterns.

J Trauma Acute Care Surg 2017 05;82(5):853-860

From Beth Israel Deaconess Medical Center, Harvard Medical School (K.I., I.R., J.Z., D.G., M.D., L.E.D., C.J.H.), Boston, Massachusetts; Koch Institute, Massachusetts Institute of Technology (I.R.), Cambridge, Massachusetts; Tanjin Medical University (J.Z.), China.

Background: Nosocomial pneumonias are common in trauma patients and so interventions to prevent and treat nosocomial pneumonia may improve outcomes. Our prior work strongly suggests that tissue injury predisposes to infections like nosocomial pneumonia because mitochondrial debris originating from injured cells contains damage-associated molecular patterns that can reduce neutrophil (PMN) migration into the airway and diminish PMN function in response to bacterial inoculation of the airway. This suggested that putting exogenous "normal" PMN into the airway might be beneficial.

Methods: Postinjury pneumonia (PNA) commonly arises in two groups, early, community-acquired PNA (CAP) and later hospital-acquired PNA (HAP). Posttraumatic early-onset CAP and late-onset HAP were modeled in CD-1 mice using Staphylococcus aureus or Pseudomonas aeruginosa instilled intratracheal (i.t.) at clinically relevant times with or without extrapulmonary injuries mimicked by an intraperitoneal application of mitochondrial damage-associated molecular patterns. We applied bone marrow-derived PMN (BM-PMN) intratracheally to assess their effect on bacterial clearance in the lung.

Results: BM-PMN instillation i.t. had no untoward clinical effects on recipient animals. In both the early/CAP and late/HAP models, clearance of the bacterial inoculum from the lung was suppressed by mitochondrial debris and restored to uninjured levels by i.t. instillation of exogenous BM-PMN. Furthermore, PMN instillation cleared the inoculum of P. aeruginosa that could not be cleared by uninjured mice. Instillation of PMN into the lung, even across strains (CD-1 vs. C57BL/6) had no injurious effect.

Conclusion: These initial studies suggest PMN instillation (i.t.) is worthy of further study as a potential adjunctive therapy aimed at decreasing the morbidity of lung infections in trauma patients. Moreover, PMN instillation (i.t.) may represent a unique means of preventing or treating pneumonia after serious injury that is completely independent of the need for antibiotic use.
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http://dx.doi.org/10.1097/TA.0000000000001413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405734PMC
May 2017

The role of carbon monoxide and heme oxygenase in the prevention of sickle cell disease vaso-occlusive crises.

Am J Hematol 2017 Jun 29;92(6):569-582. Epub 2017 Apr 29.

University of Minnesota, 420 Delaware Street SE, MMC 480, Minneapolis, MN, 55455, USA.

Sickle Cell Disease (SCD) is a painful, lifelong hemoglobinopathy inherited as a missense point mutation in the hemoglobin (Hb) beta-globin gene. This disease has significant impact on quality of life and mortality, thus a substantial medical need exists to reduce the vaso-occlusive crises which underlie the pathophysiology of the disease. The concept that a gaseous molecule may exert biological function has been well known for over one hundred years. Carbon monoxide (CO), although studied in SCD for over 50 years, has recently emerged as a powerful cytoprotective biological response modifier capable of regulating a host of physiologic and therapeutic processes that, at low concentrations, exerts key physiological functions in various models of tissue inflammation and injury. CO is physiologically generated by the metabolism of heme by the heme oxygenase enzymes and is measurable in blood. A substantial amount of preclinical and clinical data with CO have been generated, which provide compelling support for CO as a potential therapeutic in a number of pathological conditions. Data underlying the therapeutic mechanisms of CO, including in SCD, have been generated by a plethora of in vitro and preclinical studies including multiple SCD mouse models. These data show CO to have key signaling impacts on a host of metallo-enzymes as well as key modulating genes that in sum, result in significant anti-inflammatory, anti-oxidant and anti-apoptotic effects as well as vasodilation and anti-adhesion of cells to the endothelium resulting in preservation of vascular flow. CO may also have a role as an anti-polymerization HbS agent. In addition, considerable scientific data in the non-SCD literature provide evidence for a beneficial impact of CO on cerebrovascular complications, suggesting that in SCD, CO could potentially limit these highly problematic neurologic outcomes. Research is needed and hopefully forthcoming, to carefully elucidate the safety and benefits of this potential therapy across the age spectrum of patients impacted by the host of pathophysiological complications of this devastating disease.
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http://dx.doi.org/10.1002/ajh.24750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723421PMC
June 2017

Heme oxygenase and carbon monoxide protect from muscle dystrophy.

Skelet Muscle 2016 11 28;6(1):41. Epub 2016 Nov 28.

Cardiovascular Institute and Institute Diabetes Obesity and Metabolism, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, 11th floor, 3400 Civic Blvd, Philadelphia, 19104, PA, USA.

Background: Duchenne muscle dystrophy (DMD) is one of the most common lethal genetic diseases of children worldwide and is 100% fatal. Steroids, the only therapy currently available, are marred by poor efficacy and a high side-effect profile. New therapeutic approaches are urgently needed.

Methods: Here, we leverage PGC-1α, a powerful transcriptional coactivator known to protect against dystrophy in the mdx murine model of DMD, to search for novel mechanisms of protection against dystrophy.

Results: We identify heme oxygenase-1 (HO-1) as a potential novel target for the treatment of DMD. Expression of HO-1 is blunted in the muscles from the mdx murine model of DMD, and further reduction of HO-1 by genetic haploinsufficiency worsens muscle damage in mdx mice. Conversely, induction of HO-1 pharmacologically protects against muscle damage. Mechanistically, HO-1 degrades heme into biliverdin, releasing in the process ferrous iron and carbon monoxide (CO). We show that exposure to a safe low dose of CO protects against muscle damage in mdx mice, as does pharmacological treatment with CO-releasing molecules.

Conclusions: These data identify HO-1 and CO as novel therapeutic agents for the treatment of DMD. Safety profiles and clinical testing of inhaled CO already exist, underscoring the translational potential of these observations.
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http://dx.doi.org/10.1186/s13395-016-0114-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126804PMC
November 2016

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival.

Circ Res 2016 06;118(12):1940-1959

Inserm, U955, Equipe 12, Créteil, 94000, France.

Understanding the processes governing the ability of the heart to repair and regenerate after injury is crucial for developing translational medical solutions. New avenues of exploration include cardiac cell therapy and cellular reprogramming targeting cell death and regeneration. An attractive possibility is the exploitation of cytoprotective genes that exist solely for self-preservation processes and serve to promote and support cell survival. Although the antioxidant and heat-shock proteins are included in this category, one enzyme that has received a great deal of attention as a master protective sentinel is heme oxygenase-1 (HO-1), the rate-limiting step in the catabolism of heme into the bioactive signaling molecules carbon monoxide, biliverdin, and iron. The remarkable cardioprotective effects ascribed to heme oxygenase-1 are best evidenced by its ability to regulate inflammatory processes, cellular signaling, and mitochondrial function ultimately mitigating myocardial tissue injury and the progression of vascular-proliferative disease. We discuss here new insights into the role of heme oxygenase-1 and heme on cardiovascular health, and importantly, how they might be leveraged to promote heart repair after injury.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.306588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905590PMC
June 2016

Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth.

Oncotarget 2016 Apr;7(17):23919-32

Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

We hypothesized that tumor-associated macrophages (TAMs) are controlled by the diffusible gas carbon monoxide (CO). We demonstrate that induction of apoptosis in lung tumors treated with low doses of CO is associated with increased CD86 expression and activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (Erk) 1/2 pathway in tumor microenvironment. Presence of CD86-positive cells was required for the anti-tumoral effects of CO in established A549 xenografts. We show that the effects of CO on tumor stroma and reprogramming of macrophages towards the anti-tumoral phenotype is mediated by reactive oxygen species (ROS)-dependent activation of MAPK/Erk1/2-c-myc pathway as well as Notch 1-dependent negative feedback on the metabolic enzyme heme oxygenase-1 (HO-1). We find a similar negative correlation between HO-1 and active MAPK-Erk1/2 levels in human lung cancer specimens.In summary, we describe novel non-cell autonomous mechanisms by which the diffusible gas CO dictates changes in the tumor microenvironment through the modulation of macrophages.
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http://dx.doi.org/10.18632/oncotarget.8081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029674PMC
April 2016
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