Targeting lung heme iron by aerosol hemopexin adminstration in sickle cell disease pulmonary hypertension

被引：0

作者：

Lucero, Melissa J. ^{[1
]}

Lisk, Christina ^{[1
]}

Cendali, Francesca ^{[2
]}

Swindle, Delaney ^{[1
]}

Setua, Saini ^{[3
]}

Thangaraju, Kiruphagaran ^{[3
]}

Pak, David I. ^{[1
]}

O'Boyle, Quintin ^{[4
]}

Lu, Shuwei ^{[5
]}

Tolson, Robert ^{[1
]}

Zaeske, Seth ^{[1
]}

Rana, Nishant ^{[1
]}

Khan, Saqib ^{[1
]}

Westover, Natalie ^{[1
]}

Davizoncastillo, Pavel ^{[6
]}

George, Gemlyn ^{[7
]}

Hassell, Kathryn ^{[7
]}

Nuss, Rachelle ^{[7
]}

Brinkman, Nathan ^{[8
]}

Gentinetta, Thomas ^{[9
,10
]}

Palmer, Andre F.

D'Alessandro, Angelo ^{[2
]}

Buehler, Paul W. ^{[3
]}

Irwin, David C. ^{[1
]}

机构：

[1] Univ Colorado, Anschutz Med Campus Sch Med, Cardiovasc Pulm Res CVP Grp,Pediat, Translat Res Lab Red Blood Cell Dis & Hypoxia rela, Aurora, CO 80045 USA

[2] Univ Colorado Anschutz Med Campus, Dept Biochem & Mol Genet, Aurora, CO 80309 USA

[3] Univ Maryland, Sch Med, Ctr Blood Oxygen Transport & Hemostasis, Dept Pediat, Baltimore, MD 21201 USA

[4] Ohio State Univ, Coll Engn, Dept Biomed Engn, Columbus, OH USA

[5] Ohio State Univ, William G Lowrie Dept Chem & Biomol Engn, Columbus, OH 43210 USA

[6] Univ Washington, Seattle Childrens Hosp, Bloodworks Northwest, Seattle, WA USA

[7] Univ Colorado, Denver Sch Med, Anschutz Med Campus,Colorado Sickle Cell Treatment, Sch Med,DiV Hematol, , USA, Aurora, CO USA

[8] CSL Behring LLC, Plasma Prot Res & Dev, Kankakee, IL USA

[9] CSL Behring, CSL Biol Res Ctr, Bern, Switzerland

[10] Sitem Insel, Swiss Inst Translat & Entrepreneurial Med, Bern, Switzerland

来源：

FREE RADICAL BIOLOGY AND MEDICINE | 2025年 / 229卷

关键词：

BLOOD-FLOW; COMPLICATIONS; HEMOGLOBIN; OXIDATION; HEMOLYSIS; DEATH; RISK;

D O I：

10.1016/j.freeradbiomed.2025.01.045

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Lung tissue from human patients and murine models of sickle cell disease pulmonary hypertension (SCD-PH) show perivascular regions with excessive iron accumulation. The iron accumulation arises from chronic hemolysis and extravasation of hemoglobin (Hb) into the lung adventitial spaces, where it is linked to nitric oxide depletion, oxidative stress, inflammation, and tissue hypoxia, which collectively drive SCD-PH. Here, we tested the hypothesis that intrapulmonary delivery of hemopexin (Hpx) to the deep lung is effective at scavenging heme-iron and attenuating the progression of SCD-PH. Herein, we evaluated in a murine model of hemolysis driven SCD-PH, if intrapulmonary Hpx administration bi-weekly for 10 weeks improves lung iron deposition, exercise tolerance, cardiovascular function, and multi-omic indices associated with SCD-PH. Data shows Hpx delivered with a micro-sprayer deposits Hpx in the alveolar regions. Hpx extravasates into the perivascular compartments but does not diffuse into the circulation. Histological examination shows Hpx therapy decreased lung iron deposition, 4-HNE, and HO-1 expression. This was associated with improved exercise tolerance, cardiopulmonary function, and multi-omic profile of whole lung and RV tissue. Our data provides proof of concept that treating lung heme-iron by direct administration of Hpx to the lung attenuates the progression of PH associated with SCD.

引用

页码：458 / 473

页数：16

共 45 条

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