Attenuation of heme in hemolysis-induced PH. (A-B) HCP1 expression: HCP1 expression is significantly increased in NFU1 rat lungs, indicating an increased availability of free heme to vascular cells (n = 6). (C-D) Barrier dysfunction: FITC-dextran extravasation is markedly increased in the lungs of NFU1 rats, indicating barrier dysfunction. Using an HCP-1 inhibitor, sulfasalazine (SL) in NFU1 rats significantly decreased FITC-dextran extravasation, indicating that preventing the cellular entry of free heme attenuates barrier dysfunction. Scale bar, 10 mm (n = 8-10). (E) RVSP: RVSP is significantly elevated in NFU1 rats and is attenuated after SL treatment, showing that controlling free heme entry can attenuate PH (n = 8). (F) Fulton index: the elevated Fulton index observed in NFU1 rats is not significantly reduced by SL treatment (n = 7-8). (G-H) Vascular remodeling: severe vascular remodeling in NFU1 rats is significantly reversed by SL treatment. Scale bar, 100 μm (n = 4-5). (I) Schematic overview: this illustrates how MD, leading to reduced ATP levels, impairs the clearance of nuclei and organelles in RTC, increasing their susceptibility to stress and subsequent hemolysis. The resulting free heme entry into cells contributes to barrier dysfunction, vascular leakage, and pulmonary arterial hypertension (PAH). LA supplementation improves mitochondrial function, enhances reticulocyte maturation, and prevents hemolysis. SL treatment blocks heme entry, mitigating barrier dysfunction and PAH progression. A significance level of P < .05 was considered for all comparisons. An unpaired t test was used for panel A, whereas a 1-way analysis of variance of selected columns (WT vs NFU1 and NFU1 vs SL) followed by Bonferroni post hoc test was applied for panels C-H. ATP, adenosine triphosphate; FITC, fluorescein isothiocyanate; RTC, reticulocytes.
Figure 2.

Attenuation of heme in hemolysis-induced PH. (A-B) HCP1 expression: HCP1 expression is significantly increased in NFU1 rat lungs, indicating an increased availability of free heme to vascular cells (n = 6). (C-D) Barrier dysfunction: FITC-dextran extravasation is markedly increased in the lungs of NFU1 rats, indicating barrier dysfunction. Using an HCP-1 inhibitor, sulfasalazine (SL) in NFU1 rats significantly decreased FITC-dextran extravasation, indicating that preventing the cellular entry of free heme attenuates barrier dysfunction. Scale bar, 10 mm (n = 8-10). (E) RVSP: RVSP is significantly elevated in NFU1 rats and is attenuated after SL treatment, showing that controlling free heme entry can attenuate PH (n = 8). (F) Fulton index: the elevated Fulton index observed in NFU1 rats is not significantly reduced by SL treatment (n = 7-8). (G-H) Vascular remodeling: severe vascular remodeling in NFU1 rats is significantly reversed by SL treatment. Scale bar, 100 μm (n = 4-5). (I) Schematic overview: this illustrates how MD, leading to reduced ATP levels, impairs the clearance of nuclei and organelles in RTC, increasing their susceptibility to stress and subsequent hemolysis. The resulting free heme entry into cells contributes to barrier dysfunction, vascular leakage, and pulmonary arterial hypertension (PAH). LA supplementation improves mitochondrial function, enhances reticulocyte maturation, and prevents hemolysis. SL treatment blocks heme entry, mitigating barrier dysfunction and PAH progression. A significance level of P < .05 was considered for all comparisons. An unpaired t test was used for panel A, whereas a 1-way analysis of variance of selected columns (WT vs NFU1 and NFU1 vs SL) followed by Bonferroni post hoc test was applied for panels C-H. ATP, adenosine triphosphate; FITC, fluorescein isothiocyanate; RTC, reticulocytes.

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