Targeted Therapy of Acute Chest Syndrome with Recombinant Heme Oxygenase-1 Revealed By the Resistance of Young Transgenic Sickle Cell Mice to Heme-Induced Acute Lung Injury
| Autor: | Rimi Hazra, Bohong Zhang, Solomon F. Ofori-Acquah, Samit Ghosh, Matthew Crouthamel, Bethany Flage, Joseph Sypek, Sun Xiuxia, Clark Pan |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_specialty
Respiratory distress business.industry Immunology Hemopexin Cell Biology Hematology Lung injury medicine.disease Biochemistry Acute chest syndrome Sickle cell anemia Heme oxygenase chemistry.chemical_compound Endocrinology chemistry Internal medicine medicine business Heme Hemin |
| Zdroj: | Blood. 134:74-74 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Acute chest syndrome (ACS) is a major pulmonary complication of sickle cell disease (SCD) with currently no mechanistic-based therapies. Although ACS is more frequent in childhood, survival among children 1-9 years is ~10-fold higher compared to adults 20 years and older. Hitherto, mechanisms responsible for the high ACS survival in children have not been defined. We previously reported that acute elevation of circulating heme causes a TLR4-dependant lethal acute lung injury (ALI) in transgenic mice with homozygous SCD (SS) reminiscent of severe ACS (Ghosh et al., J Clin Invest, 2013). In the current study we discovered that young (4-6 weeks) and adult (12 weeks) SS mice suffer comparable severity of hemolytic crises when challenged with intravenous hemin (35 μmoles/kg bw). However, virtually none of the young mice develop ALI while nearly all the adults succumb with respiratory failure. We discovered that young SS mice rapidly clear excess heme from the circulation suggesting this was the reason for their resistance to intravenous hemin. Interestingly, young SS mice have significantly lower plasma hemopexin levels than adult SS mice, which excludes the classical heme scavenging pathway as the reason for their heme resistance. Previous studies have linked genetically high heme oxygenase-1 (HO-1) expression with low-risk of ACS, and raised steady-state levels of plasma heme with high-risk ACS in children. To explore these associations further, we studied a large cohort of patients and discovered for the first time that the concentration of plasma HO-1 in SCD children 1-9 yrs is 2-fold higher than adults 20 yrs and older (23.6±1.1, n=191 versus mean 10.7±0.6, n=67); these findings were phenocopied in transgenic SS mice. Plasma fractionization experiments revealed that HO-1 co-localizes with the enzymatic and co-factor machinery required for heme degradation indicating that heme can be degraded in the blood circulation. To test this idea ~3 weeks old SS mice were treated with the HO-1 inhibitor tin protoporphyrin (SnPP) or vehicle, and challenged with intravenous hemin five days later to induce ALI/ACS. Plasma HO activity declined by ~76% in SnPP-treated mice and was unchanged in the vehicle treated animals (n=12-14, p Disclosures Ofori-Acquah: Shire Human Genetic Therapies Inc: Other: Financial Relationship. |
| Databáze: | OpenAIRE |
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