Carbon Monoxide Therapy Research Articles

Tumor-Targeted CO Nanodelivery System Design and Therapy for Hepatocellular Carcinoma.

In recent years, carbon monoxide (CO) has garnered increased attention as a novel green therapy for hepatocellular carcinoma (HCC) treatment. However, the CO donor is still limited in clinical application due to its lack of targeted ability and unstable release rate. Here, self-assembled amphiphilic nanomicelles glucose-polyethylene glycol (PEG)-lipoic acid (LA)-Fe2(CO)6 (Glu-Fe2(CO)6) are first designed as a CO donor and synthesized via a chemical method, combining glucose with Fe2(CO)6 through PEG-LA. Some advantages of this tumor-targeted Glu-Fe2(CO)6 delivery system include (I) good water-solubility, (II) the glutathione responsive CO slow release, (III) the active tumor-targeted ability of glucose as targeted ligands, and (IV) outstanding efficacy of antitumor and safety of CO therapy of HCC both in vitro and in vivo. These findings suggest that Glu-Fe2(CO)6 nanomicelles hold promise for enhancing antitumor therapeutic capabilities, presenting a novel tumor-targeted delivery strategy in gas therapy for HCC treatment.

H2S-Responsive NIR-II Fluorescent Nanozyme that Regulates Tumor Microenvironment for Activatable Synergistic CO Therapy/Catalytic Therapy/Immunotherapy.

Nanozyme catalytic therapy triggered by the tumor microenvironment (TME)-responsive enzyme-like catalytic activities is an emerging approach for tumor treatment. However, the poor catalytic efficiency of nanozymes in tumors and the toxic side effects on normal tissues limit their further development, primarily due to the limited uptake and penetration depth of nanozyme in tumor tissues. Here, a tumor-targeting TME and electric field stimuli-responsive nanozyme (AgPt@CaCO3-FA) is developed, which is capable of catalyzing the generation of ROS to induce cell death and releasing carbon monoxide (CO) specifically in tumor tissues for on-demand CO therapy and immunotherapy. Benefiting from the endogenous H2S activated NIR-II fluorescence (FL) imaging guidance, AgPt@CaCO3-FA can be delivered into the deeper site of tumor tissues resulted from the TME regulation via generated CO during the electrolysis process to improve the catalytic efficiency of nanozymes in tumors. Moreover, CO effectively relieve immunosuppression TME via reeducating tumor-supportive M2-like macrophages to tumoricidal M1-like macrophages and induce mitochondrial dysfunction by reducing mitochondrial membrane potential, triggering tumor cells apoptosis. The enzyme-like activities combined with CO therapy arouse distinct immunogenic cell death (ICD) effect. Therefore, AgPt@CaCO3-FA permits synergistic CO gas, catalytic therapy and immunotherapy, effectively eradicating orthotopic breast tumors and preventing tumor metastasis and recurrence.

Abstract A114: Low-dose carbon monoxide halts pancreatic cancer metastasis

Abstract Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. Pancreatic ductal adenocarcinoma (PDAC) accounts for about 90% of pancreatic cancer cases. Over the last 30 years, standard care of chemotherapy only extends the survival of metastatic pancreatic cancer patients for a few months. Despite years of remarkable innovations in cancer treatment, the 5-year survival rate of PDAC has remained dismal. The recalcitrant nature of PDAC to available treatments highlights an urgent need for novel therapeutics in order to substantially increase survival. Carbon monoxide (CO) is produced endogenously in humans and has been established as an important, biologically active signaling molecule. Accumulating evidence suggests the therapeutic applications of safe, low-dose CO for various diseases. We evaluate the therapeutic effect of CO on pancreatic cancer progression. We show that 250 ppm CO inhibits migration of pancreatic cancer. We demonstrate that low-dose CO suppresses metastasis of PDAC in an orthotopic mouse model of liver metastasis and a spontaneous PDAC metastasis mouse model after the removal of primary tumor xenograft tumors. Mechanistically, low-dose CO blocks transcription of heme importers, leading to diminished intracellular heme levels and a heme-regulated enzyme, cytochrome P4501B1 (CYP1B1). Either supplementing heme or overexpressing CYP1B1 reverses the anti-migration effect of low-dose CO. Altogether, low-dose CO therapy inhibits pancreatic cancer cell migration, prevents disseminated cancer cells from expanding into gross metastases, and improves survival in pre-clinical mouse models of metastasis. Citation Format: Tiantian Zhang, George Zhang, Xiang Chen, Zhengming Chen, Adrian Y. Tan, Anthony Lin, Cheryl Zhang, Guoan Zhang, Jenny Xiang, Erika Hissong, Yao-Tseng Chen, Nancy Du. Low-dose carbon monoxide halts pancreatic cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A114.

Tumor microenvironment-responsive delivery nanosystems reverse immunosuppression for enhanced CO gas/immunotherapy.

Carbon monoxide (CO) gas therapy demonstrates great potential to induce cancer cell apoptosis and antitumor immune responses, which exhibits tremendous potential in cancer treatment. However, the therapeutic efficacy of CO therapy is inhibited by the immunosuppressive tumor microenvironment (TME). Herein, a facile strategy is proposed to construct hollow-structured rough nanoplatforms to boost antitumor immunity and simultaneously reverse immunosuppression by exploring intrinsic immunomodulatory properties and morphological optimization of nanomaterials. The TME-responsive delivery nanosystems (M-RMH) are developed by encapsulating the CO prodrug within hollow rough MnO2 nanoparticles and the subsequent surface functionalization with hyaluronic acid (HA). Rough surfaces are designed to facilitate the intrinsic properties of HA-functionalized MnO2 nanoparticles (RMH) to induce dendritic cell maturation and M1 macrophage polarization by STING pathway activation and hypoxia alleviation through enhanced cellular uptake. After TME-responsive degradation of RMH, controlled release of CO is triggered at the tumor site for CO therapy to activate antitumor immunity. More importantly, RMH could modulate immunosuppressive TME by hypoxia alleviation. After the combination with aPD-L1-mediated checkpoint blockade therapy, robust antitumor immune responses are found to inhibit both primary and distant tumors. This work provides a facile strategy to construct superior delivery nanosystems for enhanced CO/immunotherapy through efficient activation of antitumor immune responses and reversal of immunosuppression.

Biofilm microenvironment-responsive polymeric CO releasing micelles for enhanced amikacin efficacy

Biofilm-associated infections (BAI) have posed serious threats to public health. Novel therapy based on carbon monoxide (CO) is being increasingly appreciated. However, CO therapy like inhaled gas treatment was impeded owing to its low bioavailability. Besides, the direct use of CO releasing molecules (CORM) showed low therapeutic efficacy in BAI. Therefore, it is vital to improve the efficiency of CO therapy. Herein, we proposed polymeric CO releasing micelles (pCORM) from self-assembly of amphiphilic copolymers containing CORM bearing block as hydrophobic part and acryloylmorpholine block as hydrophilic part. The catechol modified CORM were conjugated through pH cleavable boronate ester bonds and releasing CO passively under biofilm microenvironment. When combined with subminimal inhibitory concentration antibiotic amikacin, pCORM could significantly enhance its bactericidal efficiency against biofilm-encapsulated multidrug-resistant bacteria, representing a promising approach to combat BAI.

Renal Clearable Catalytic 2D Au-Porphyrin Coordination Polymer Augmented Photothermal-Gas Synergistic Cancer Therapy.

As a gasotransmitter, carbon monoxide (CO) possesses antitumor activity by reversing the Warburg effect at higher concentrations. The targeted delivery of carbon monoxide-releasing molecules (CORMs) using nanomaterials is an appealing option for CO administration, but how to maintain CO above the threshold concentration in tumor tissue remains a challenge. Herein, a nanozyme-catalyzed cascade reaction is proposed to promote CO release for high-efficacy photothermal therapy (PTT)-combined CO therapy of cancer. A gold-based porphyrinic coordination polymer nanosheet (Au0 -Por) is synthesized to serve as a carrier for CORM. It also possesses excellent glucose oxygenase-like activity owing to ultrasmall zero-valent gold atoms on the nanosheet. The catalytically generated H2 O2 can efficiently catalyze CORM decomposition, which enables in situ generation of sufficient CO for gas therapy. In vivo, the Au0 -Por nanosheets-enhanced photoacoustic imaging (PAI) and fluorescence imaging collectively demonstrate high tumor-targeting efficiency and nanomaterial retention. Proven to have augmented therapeutic efficacy, the nanoplatform can also be easily degraded and excreted through the kidney, indicating good biocompatibility. Thus, the application of rational designed Au0 -Por nanosheet with facile approach and biodegradable property to PAI-guided synergistic gas therapy can provide a strategy for the development of biocompatible and highly effective gaseous nanomedicine.

Carbon monoxide therapy: a promising strategy for cancer.

Cancer is one of the acute life-threatening diseases endangering the whole of humanity. The treatment modalities for cancer are various. However, in most cases, a single treatment choice provides multiple side effects, poor targeting, and ineffective treatment. In recent years, the physiological regulatory function of carbon monoxide (CO) in the cancer process has been reported gradually, and CO-related nano-drugs have been explored. It shows better application prospects in cancer treatment and provides new ideas for treatment. The present review introduces the pathophysiological role of CO. The recent advances in cancer therapy, such as CO-mediated gas therapy, combined application of CO chemotherapy, photodynamic therapy (PDT), photothermal therapy (PTT), and immunotherapy, are described. Current challenges and future developments in CO-based treatment are also discussed. This review provides comprehensive information on recent advances in CO therapy and also some valuable guidance for promoting the progress of gas therapy nanomedicine.

Second Near-infrared Light-activatable CO nanogenerator for enhanced cancer Photo-theranostics

Carbon monoxide (CO) has received substantial attention for its many beneficial functions in multiple major diseases. However, precise delivery and controllable release of CO are crucial for CO therapy in cancer but remain technically challenging. Herein, an NIR-II light-controlled CO nanogenerator is described as a new cancer photo-theranostic (Pd@PdCO-MOF) via photoacoustic imaging guided photothermal/CO-combined therapy. This nanogenerator is based on an NIR-II-photothermal palladium nanosheet core and a porphyrin-palladium metal–organic framework (Pd-MOF) shell, which can coordinate/load large amounts of CO with single-atom palladium. Meanwhile, the obtained photo-theranostic exhibited excellent release of CO on demand after NIR-II photoactivation. The produced CO molecules successfully increased the sensitivity of cancer cell to photothermal therapy (PTT). Mechanistically, the CO-assisted PTT efficiently inhibited cancer development by decreasing the intracellular ATP levels, downregulating heat shock protein expression, increasing the expression of cytochrome C, and subsequently activating the apoptosis pathway. Guided by photoacoustic imaging, the obtained Pd@PdCO-MOF nanoplatform demonstrated high therapeutic efficacy in vitro and in vivo through the photothermal-CO combination therapy, which may provide a new strategy for cancer theranostics.

Low-dose carbon monoxide suppresses metastatic progression of disseminated cancer cells

Low-dose carbon monoxide (CO) is under investigation in clinical trials to treat non-cancerous diseases and has an excellent safety profile. Due to early detection and cancer awareness, an increasing number of cancer patients are diagnosed at early stages, when potentially curative surgical resection can be done. However, many patients ultimately experience recurrence. Here, we evaluate the therapeutic effect of CO on metastatic cancer progression. We show that 250 ppm CO inhibits the migration of multiple types of cancer cell lines, including breast, pancreatic, colon, prostate, liver, and lung cancer and reduces the ability to adhere to fibronectin. We demonstrate that in mouse models, 250 ppm inhaled CO inhibits lung metastasis of breast cancer and liver metastasis of pancreatic cancer. Moreover, low-dose CO suppresses recurrence and increases survival after surgical removal of primary pancreatic cancer in mice. Mechanistically, low-dose CO blocks transcription of heme importers, leading to diminished intracellular heme levels and a heme-regulated enzyme, cytochrome P4501B1 (CYP1B1). Either supplementing heme or overexpressing CYP1B1 reverses the anti-migration effect of low-dose CO. Taken together, low-dose CO therapy inhibits cell migration, reduces adhesion to fibronectin, prevents disseminated cancer cells from expanding into gross metastases, and improves survival in pre-clinical mouse models of metastasis.

Theranostic Trigger-Responsive Carbon Monoxide-Generating Microbubbles.

Carbon monoxide (CO) is a gaseous signaling molecule that modulates inflammation, cell survival, and recovery after myocardial infarction. However, handling and dosing of CO as a compressed gas are difficult. Here, light-triggerable and magnetic resonance imaging (MRI)-detectable CO release from dimanganese decacarbonyl (CORM-1) are demonstrated, and the development of CORM-1-loaded polymeric microbubbles (COMB) is described as an ultrasound (US)- and MRI-imageable drug delivery platform for triggerable and targeted CO therapy. COMB are synthesized via a straightforward one-step loading protocol, present a narrow size distribution peaking at 2µm, and show excellent performance as a CORM-1 carrier and US contrast agent. Light irradiation of COMB induces local production and release of CO, as well as enhanced longitudinal and transversal relaxation rates, enabling MRI monitoring of CO delivery. Proof-of-concept studies for COMB-enabled light-triggered CO release show saturation of hemoglobin with CO in human blood, anti-inflammatory differentiation of macrophages, reduction of hypoxia-induced reactive oxygen species (ROS) production, and inhibition of ischemia-induced apoptosis in endothelial cells and cardiomyocytes. These findings indicate that CO-generating MB are interesting theranostic tools for attenuating hypoxia-associated and ROS-mediated cell and tissue damage in cardiovascular disease.

Manganese Carbonyl-Loaded Hollow Mesoporous Silica Nanoparticles Coated with Neutrophil Membranes for Acute Kidney Injury Therapy

Acute kidney injury (AKI) has a very high incidence in hospitalized patients, but it lacks effective therapy clinically. Its pathogenesis is associated with capillary hypoperfusion around renal tubules, production of reactive oxygen free radicals (ROS), and infiltration of inflammatory cells. Endogenous carbon monoxide (CO) can protect cells or organs by vasodilation, anti-inflammation, and reducing oxidative stress injury. However, direct exogenous CO supplementation is difficult to control the exact dose, and excessive CO has obvious toxicity, which is difficult to be applied in clinical treatment. In this study, we constructed H2O2-responsive nanomedicine for CO therapy of AKI by loading manganese carbonyl (MnCO) onto the hollow mesoporous silicon nanoparticles (hMSN), which were coated with a neutrophil membrane with the insertion of phosphatidylserine (PS) into the membrane surface (MnCO@hMSN@NM-PS). MnCO@hMSN@NM-PS was located in the renal tubules of AKI through the biomimetic chemotaxis of the neutrophil membrane to the inflammation site and the active binding of PS to kidney injury molecule-1 (KIM-1), which was overexpressed in damaged renal tubular epithelial cells. MnCO@hMSN@NM-PS had a good protective effect on oxidative damage of renal tubular cells in vitro and glycerol-induced AKI in vivo. MnCO@hMSN@NM-PS offers hope for the treatment of AKI.

X-ray-Triggered CO Release Based on GdW10/MnBr(CO)5 Nanomicelles for Synergistic Radiotherapy and Gas Therapy.

Carbon monoxide (CO) therapy has become a hot topic in the field of gas therapy because of its application prospect in the treatment of various diseases. Due to the high affinity for human hemoglobin, the main challenge of CO-loaded nanomedicine is the lack of selectivity and toxicity in the delivery process. Although many commercial CO-releasing molecules (CORMs) have been widely developed because of their ability to deliver CO, CORMs still have some disadvantages, including difficult on-demand controlled CO release, poor solubility, and potential toxicity, which are limiting their further application. Herein, an X-ray-triggered CO-releasing nanomicelle system (GW/MnCO@PLGA) based on GdW10 nanoparticles (NPs) (GW) and MnBr(CO)5 (MnCO) encapsulating in the poly(lactic-co-glycolic acid) (PLGA) polymer was constructed for synergistic CO radiotherapy (RT). The production of strongly oxidative superoxide anion (O2-•) active species can lead to cell apoptosis under the X-ray sensitization of GW. Moreover, strongly oxidative O2-• radicals further oxidize and compete with the Mn center, resulting in the on-demand release of CO. The radio/gas therapy synergy to enhance the efficient tumor inhibition of the nanomicelles was investigated in vivo and in vitro. Therefore, the establishment of an X-ray-triggered controlled CO release system has great application potential for further synergistic RT CO therapy in deep tumor sites.

Multifunctional carbon monoxide nanogenerator as immunogenic cell death drugs with enhanced antitumor immunity and antimetastatic effect

The limited effect of immune checkpoint blockade (ICB) immunotherapy is subjected to the immuno-suppressive tumor microenvironment (TME). It is still a challenge to reverse the immune-suppressive state in clinical cancer therapy. Immunogenic cell death (ICD) is a way for inducing the therapeutical tumor immune system. In this work, carbon monoxide (CO) gas therapy is used to boost antitumor immunity for tumor control, metastasis and recurrence prevention. Briefly, CO2-g–C3N4–Au@ZIF-8@F127 (CCAZF) is proposed to integrate gas therapy and immunotherapy into a photocatalytic nanogenerator for overcoming the limitations of monotherapy. CCAZF exhibits a highly effective light-controllable release behavior of CO, which gradually aggravates the oxidative stress in tumor cells to induce ICD. With the induction of ICD, CO therapy enhances immune responses and enables efficient immune cells activated. When combined with ICB, CCAZF displays an enhanced immune effect, which mediates the regression of primary and distal tumors. This strategy of in-situ photocatalytic CO therapy furthest avoids the toxicity from CO leakage and provides a new method to design novel ICD inducers.

Carbon Monoxide Therapy Using Hybrid Carbon Monoxide-Releasing/Nrf2-Inducing Molecules through a Neuroprotective Lens

Carbon monoxide (CO) has long been known for its toxicity. However, in recent decades, new applications for CO as a therapeutic compound have been proposed, and multiple forms of CO therapy have since been developed and studied. Previous research has found that CO has a role as a gasotransmitter and promotes anti-inflammatory and antioxidant effects, making it an avenue of interest for medicine. Such effects are possible because of the Nrf2/HO1 pathway, which has become a target for therapy development because its activation also leads to CO release. Currently, different forms of treatment involving CO include inhaled CO (iCO), carbon monoxide-releasing molecules (CORMs), and hybrid carbon monoxide-releasing molecules (HYCOs). In this article, we review the progression of CO studies to develop possible therapies, the possible mechanisms involved in the effects of CO, and the current forms of therapy using CO.

A “controlled CO release” and “pro-angiogenic gene” dually engineered stimulus-responsive nanoplatform for collaborative ischemia therapy

Ischemic injury is mostly caused by insufficient blood supply, excessive inflammation and increased oxidative stress. Pro-angiogenic gene delivery can foster vascular remodeling and increase blood perfusion, but the adverse ischemia microenvironment leads to inadequate therapy effect and high recurrence rate. A novel combination strategy should be developed for the effective therapy of ischemic injury via remediating microenvironment and accelerating revascularization simultaneously. Carbon monoxide (CO) exhibits multiple bio-functions, especially anti-inflammation and anti-oxidant effects, suggesting that it might be an attractive candidate for ischemia therapy. Herein, for the first time, “controlled CO release” was introduced to treat limb ischemia. We developed the controlled CO delivery nanoplatform (PR@CORM) via encapsulating CO-releasing molecule-401 by the stimulus-responsive and ECs-adhesive peptide functionalized nanocarrier. In response to oxidants, PR@CORM can intelligently release therapeutic CO gas to remediate the microenvironment, but the pro-angiogenic effect is still disappointing. We thereby combined “CO therapy” and “pro-angiogenic gene therapy” to achieve the cooperative effects for ischemia therapy. This strategy exhibits superiority in the treatment of ischemic injury through extensively normalizing the microenvironment and accelerating revascularization. The “controlled CO release” serves as a scavenger of inflammation and reactive oxygen species, and pro-angiogenic gene holds potential for ischemia therapy.

CO/chemosensitization/antiangiogenesis synergistic therapy with H2O2-responsive diselenide-containing polymer

Carbon monoxide (CO) therapy and antiangiogenesis therapy (AAT) are regarded as promising approaches for cancer treatment. However, the poor tumor targeting ability and inevitable side effects prevent their clinical application. In this study, we developed H2O2-responsive diselenide-containing micelles that combined CO therapy with chemosensitization therapy and AAT in a single system. Under the interaction of intratumoral H2O2, CO and gemcitabine (GEM) were released in situ from the micelles to reduce side effects, and CO significantly sensitized the chemotherapeutic effect of GEM by elevating the level of reactive oxygen species (ROS) in human gastric cancer AGS cells. Furthermore, diselenide bonds in the micelles were oxidized to seleninic acid in organic form, which suppressed the expressions of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) to realize AAT. This study provides an integrated solution to combine CO therapy with chemosensitization therapy and AAT together with good biocompatibility.

Upregulation of Intragraft Inflammatory Cytokine is Associated with Pulmonary Allograft Rejection in MHC-Inbred CLAWN Miniature Swine

A close link between early initiation of ischemia-reperfusion injury and subsequent immune system activation is well recognized in several organ transplants, however, large animal models to investigate the role of innate immunity in transplant tolerance and rejection have been still limited. In this study, we evaluated the association of intragraft inflammatory change and pulmonary allograft rejection using DNA-PCR typed MHC-inbred CLAWN miniature swine. As Group 1, six swine received fully MHC-mismatched lungs with 12-days of tacrolimus (35-45 ng/ml). As Group 2, three recipients were transplanted with fully MHC-mismatched lung grafts from brain-dead (BD) donors induced by subdural balloon and subsequently ventilated for 6 h before organ procurement to investigate whether BD affects the graft survival. As Group 3, the BD donor was treated with carbon monoxide (CO) for 3 hours before organ procurement, anticipating to reduce inflammatory response in the graft and then transplanted to the MHC-mismatched recipients. Graft function was assessed with blood gases drawn from the pulmonary vein of the transplanted lung and serial chest X-rays and open lung biopsy. The expression of mRNA of proinflammatory cytokines of the grafts were quantified using real-time RT-PCR. All grafts in Group 1 was rejected within 63 days (47 ± 7 days) with diffuse mononuclear infiltrates associated with intra-alveolar hemorrhage and capillary congestion, consistent with severe cellular and antibody-mediated rejection. All animals in Group 2 rejected their grafts within 35 days with accelerated development of anti-donor antibodies. CO therapy to the BD donors was dramatically effective in prolonging graft survival; all recipients accepted their grafts over 35 days (82 ± 13 vs 26 ± 5 days). PO2 of graft PV in Group 3 was significantly higher than in Group 2 (546 ± 57 vs. 349 ± 28 mmHg) associated with fewer inflammatory cell infiltrates on 2-hour and 2-day biopsies. Up-regulation of proinflammatory cytokines as early as 6h after BD induction were markedly reduced by CO inhalation. These data clearly demonstrated that upregulation of intragraft inflammatory cytokine is associated with not only early graft function but pulmonary allograft rejection in clinically relevant large animal using MHC-inbred CLAWN miniature swine.

Intelligent Metal Carbonyl Metal-Organic Framework Nanocomplex for Fluorescent Traceable H2 O2 -Triggered CO Delivery.

The recognized therapeutic benefits from carbon monoxide (CO) have caused booming attention to develop a CO therapy for various major diseases, such as cancer. However, the controlled release of CO gas and the monitoring of the CO release are vitally important to the on-demand CO administration for a safe and efficient therapy, but greatly challenging. In this work, a new CO-releasing nanocomplex was constructed by the adsorption and coordination of manganese carbonyl ([MnBr(CO)5 ], abbreviated as MnCO) with a Ti-based metal-organic framework (Ti-MOF) to realize an intratumoral H2 O2 -triggered CO release and real-time CO release monitoring by fluorescence imaging. A high CO prodrug loading capacity (0.532 g MnCO per gram Ti-MOF) is achieved due to the high surface area of Ti-MOF, and the intracellular H2 O2 -triggered CO release from the MnCO@Ti-MOF is realized to enable the nanocomplex selectively release CO in tumor cells and kill tumor cells rather than normal cells. Particularly significant is that the real-time fluorescence imaging monitoring of the CO release is realized based on an annihilation effect of the fluorescence after MnCO loading into Ti-MOF and an activation effect of the fluorescence after CO release from Ti-MOF. The quantitative relationship between the fluorescence intensity and the released CO amount is established in great favor of guiding on-demand CO administration. The results demonstrate the advantage of versatile MOFs for high efficient CO delivery and monitoring, which is critical for the improvement of the effectiveness of future therapeutic application.

Overcoming safety challenges in CO therapy – Extracorporeal CO delivery under precise feedback control of systemic carboxyhemoglobin levels

Carbon monoxide (CO) has demonstrated therapeutic potential in multiple inflammatory conditions including intensive care applications such as organ transplantation or sepsis. Approaches to translate these findings into future therapies, however, have been challenged by multiple hurdles including handling and toxicity issues associated with systemic CO delivery. Here, we describe a membrane-controlled Extracorporeal Carbon Monoxide Release System (ECCORS) for easy implementation into Extracorporeal Membrane Oxygenation (ECMO) setups, which are being used to treat cardiac and respiratory diseases in various intensive care applications. Functionalities of the ECCORS were investigated in a pig model of veno-arterial ECMO. By precisely controlling CO generation and delivery as a function of systemic carboxyhemoglobin levels, the system allows for an immediate onset of therapeutic CO-levels while preventing CO-toxicity. Systemic carboxyhemoglobin levels were profiled in real-time by monitoring exhaled CO levels as well as by pulse oximetry, enabling self-contained and automatic feedback control of CO generation within ECCORS. Machine learning based mathematical modeling was performed to increase the predictive power of this approach, laying foundation for high precision systemic CO delivery concepts of tomorrow.

Antioxidant and Cerebroprotective Roles of Carbon Monoxide (CO) Against Cerebrovascular Injury Caused by Prolonged Neonatal Asphyxia

Asphyxia occurring in the fetus and newborn infant frequently leads to hypoxic‐ischemic encephalopathy (HIE) in survivors. The neonatal brain circulatory system is compromised by asphyxia/reventilation via a mechanism that may involve oxidative stress. CO, a gaseous messenger with antioxidant properties, is produced from heme via the heme oxygenase (HO)‐catalyzed reaction. We tested the hypothesis that CO, either produced by the brain, or delivered systemically by the donor molecule CORM‐A1, has a cerebrovascular protective role during neonatal asphyxia. We developed a novel survival model of prolonged asphyxia (50 – 60 min) in newborn pigs that combines insults of severe hypoxia (PaO2, 20–30 mm Hg), hypercapnia (PaCO2, 70–80 mm Hg), and acidosis (pH, 6.9–7.0) while avoiding extreme systemic hypotension and cerebral ischemia. During the asphyxia conditions, we observed immediate and sustained activation of brain HO as detected by an elevated CO concentration in the cortical periarachnoid fluid. Cortical astrocytes are among the main sources of brain CO production in normal and asphyxiated brains. Asphyxia followed by a 60‐min reventilation with room air caused excessive formation of reactive oxygen species (ROS) in the neonatal brain. Brain oxidative stress was potentiated by the HO inhibitor tin protoporphyrin, suggesting that activation of astrocytic HO/CO during asphyxia has antioxidant effects. Administered 30 min before asphyxia, CORM‐A1 (2 mg/kg i.p.) prevented excessive ROS formation in the brain during reventilation. We tested the effects of prolonged neonatal asphyxia on cerebral vascular dilator functions after 24 and 48 h of recovery using the cranial window technique. Endothelium‐dependent vasodilatory responses to hypercapnia and bradykinin were not negatively affected by prolonged asphyxia. In contrast, astrocyte‐dependent cerebral vasodilatory responses to adenosine diphosphate (ADP) and glutamate were compromised, indicating that astrocytes are selectively injured by prolonged asphyxia. Endothelium‐ and astrocyte‐independent cerebral vascular smooth muscle functions tested by vasodilations to isoproterenol and sodium nitroprusside remained intact in post‐asphyxic newborn pigs. In CORM‐A1‐pretreated animals, prolonged asphyxia did not produce any cerebral vascular incapacities, suggesting that CO therapy protects astrocytes from asphyxia/reventilation injury. Overall, prolonged neonatal asphyxia without systemic hypotension or cerebral ischemia injures cortical astrocytes via an oxidative stress‐mediated mechanism that can be partially counteracted by activation of the endogenous HO/CO‐based antioxidant system in the brain or by CO/CORM‐A1 therapy. We propose that gaseous CO and CO donor molecules can be used as novel efficient therapeutic approaches to prevention of neonatal brain injury caused by prolonged asphyxia.Support or Funding InformationR01 NS 101717; R01 HL 034059; R01 HL 042851This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.