Sickle Erythrocytes and Platelets Augment Lung Leukotriene Synthesis with Downregulation of Anti‐Inflammatory Proteins: Relevance in the Pathology of the Acute Chest Syndrome

Abstract

Initiation, progression, and resolution of vaso-occlusive pain episodes in sickle cell disease (SCD) have been recognized as reperfusion injury, which provokes an inflammatory response in the pulmonary circulation. Some 5-lipoxygenase (5-lox) metabolites are potent vasoconstrictors in the pulmonary circulation. We studied stimulation of production of the inflammatory eicosanoids leukotrienes (LTs) and prostaglandin E 2 (PGE 2 ) by isolated rat lungs perfused with sickle (HbSS) erythrocytes. Our hypothesis is that HbSS erythrocytes produce more LTs than normal (HbAA) erythrocytes, which can induce vaso-occlusive episodes in SCD patients. Lung perfusates were collected at specific time points and purified by high-pressure liquid chromatography, and LTC 4 and PGE 2 contents were measured by enzyme-linked immunosorbent assay (ELISA). Rat lung explants were also cultured with purified HbAA and HbSS peptides, and 5-lox, cyclooxygenase 1/2, and platelet-activating factor receptor (PAFR) proteins were measured by Western blotting, while prostacyclin and LTs produced by cultured lung explants were measured by ELISA. Lung weight gain and blood gas data were not different among the groups. HbSS-perfused lungs produced more LTC 4 and PGE 2 than HbAA-perfused lungs: 10.40 AE 0.62 versus 0.92 AE 0.2 ng/g dry lung weight (mean AE SEM; P ¼ 0.0001) for LTC 4 . Inclusion of autologous platelets (platelet-rich plasma) elevated LTC 4 production to 12.6 AE 0.96 and 7 AE 0.60 ng/g dry lung weight in HbSS and HbAA perfusates, respectively. HbSS lungs also expressed more 5-lox and PAFR. The data suggest that HbSS erythrocytes and activated platelets in patient's pulmonary microcirculation will enhance the synthesis and release of the proinflammatory mediators LTC 4 and PGE 2 , both of which may contribute to onset of the acute chest syndrome in SCD.

Sickle red cells as danger signals on proinflammatory gene expression, leukotriene B4 and interleukin-1 beta production in peripheral blood mononuclear cell

“…Leukotrienes (LT) are important inflammatory mediators, and LTB 4 promotes leukocyte migration and adhesion to the vascular endothelium [71,72]. Our observation that SS-RBC increased LTB 4 production in PBMC culture in a significantly more pronounced fashion when compared to AA-RBC is corroborated by the report showing that LT production is augmented in PBMC culture challenged with SS-RBC [72], demonstrating that SS-RBC can amplify the inflammatory response by stimulating leukocyte recruitment.…”

Hypoxia-mediated impaired erythrocyte Lands’ Cycle is pathogenic for sickle cell disease

“…Of note, early studies hinted that increased LysoPC is involved in generating curvature of cell membranes 32 and mediating the formation of tubules connecting the Golgi stacks 40 41 . AA was reported to be elevated in SCD patients and is a precursor of multiple immune mediators including leukotrienes and prostaglandin 42 43 44 45 . However, the in vivo pathological significance of imbalanced Lands’ cycle-mediated increased LysoPC and AA in SCD has not been recognized prior to our studies.…”

The Natural Products Targeting on Allergic Rhinitis: From Traditional Medicine to Modern Drug Discovery

“…LTA 4 produces LTC 4 , LTD 4 , and LTE 4 or transforms into LTB 4 . LTC 4 , LTD 4 , and LTE 4 bind to cysteinyl leukotriene 1 (CystLT1) receptors, evoking chemotaxis, chemokine expression, and EC proliferation [48,49].…”