Role of heme in bromine‐induced lung injury

Lam, Adam; Vetal, Nilam; Matalon, Sadis; Aggarwal, Saurabh

doi:10.1111/nyas.13086

Cited by 34 publications

(23 citation statements)

References 49 publications

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“…Hyperoxic exposure of neonatal HO-1 knockout mice elicits a BPD phenotype that is attenuated upon activation or overexpression of HO-1 (43). In models of ARDS, HO-1 overexpression confers resistance to the development of lung injury (10,22,26,35,42). In contrast to other Nrf2-regulated genes, we have consistently observed a disproportionate increase in HO-1 levels following TXNRD1 inhibition in vitro and in a murine BPD model in vivo (25,28).…”

Section: Introductionmentioning

confidence: 66%

The thioredoxin reductase inhibitor auranofin induces heme oxygenase-1 in lung epithelial cells via Nrf2-dependent mechanisms

Dunigan

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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Thioredoxin reductase-1 (TXNRD1) inhibition effectively activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responses and attenuates lung injury in acute respiratory distress syndrome (ARDS) and bronchopulmonary dysplasia (BPD) models. Upon TXNRD1 inhibition, heme oxygenase-1 (HO-1) is disproportionally increased compared with Nrf2 target NADPH quinone oxidoreductase-1 (Nqo1). HO-1 has been investigated as a potential therapeutic target in both ARDS and BPD. TXNRD1 is predominantly expressed in airway epithelial cells; however, the mechanism of HO-1 induction by TXNRD1 inhibitors is unknown. We tested the hypothesis that TXNRD1 inhibition induces HO-1 via Nrf2-dependent mechanisms. Wild-type (WT), Nrf2, and Nrf2 cells were morphologically indistinguishable, indicating that Nrf2 can be deleted from murine-transformed club cells (mtCCs) using CRISPR/Cas9 gene editing. Hemin, a Nrf2-independent HO-1-inducing agent, significantly increased HO-1 expression in WT, Nrf2, and Nrf2. Auranofin (AFN) (0.5 µM) inhibited TXNRD1 activity by 50% and increased Nqo1 and Hmox1 mRNA levels by 6- and 24-fold, respectively, in WT cells. Despite similar levels of TXNRD1 inhibition, Nqo1 mRNA levels were not different between control and AFN-treated Nrf2 and Nrf2. AFN slightly increased Hmox1 mRNA levels in Nrf2 and Nrf2 cells compared with controls. AFN failed to increase HO-1 protein in Nrf2 and Nrf2 compared with a 36-fold increase in WT mtCCs. Our data indicate that Nrf2 is the primary mechanism by which TXNRD1 inhibitors increase HO-1 in lung epithelia. Future studies will use ARDS and BPD models to define the role of HO-1 in attenuation of lung injury by TXNRD1 inhibitors.

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Section: Introductionmentioning

confidence: 66%

The thioredoxin reductase inhibitor auranofin induces heme oxygenase-1 in lung epithelial cells via Nrf2-dependent mechanisms

Dunigan

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In humans, isolated cases of accidental inhalation of high concentrations of Br 2 have reported respiratory and myocardial injury, cardiac arrest, and circulatory collapse (40,43). However, systematic studies on effects of Br 2 inhalation are recently emerging (1,5,17,28,31,32,48,58,67,71). The National Research Council has put forth a LD 50 for mice at an exposure of 204 parts per million (ppm) Br 2 for 30 min, and human studies have shown eye and throat irritation at 1-ppm exposure for up to 8 h (44a).…”

Section: Introductionmentioning

confidence: 99%

Bromine inhalation mimics ischemia-reperfusion cardiomyocyte injury and calpain activation in rats

Ahmad

Juncos

Ahmad

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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Halogens are widely used, highly toxic chemicals that pose a potential threat to humans because of their abundance. Halogens such as bromine (Br2) cause severe pulmonary and systemic injuries; however, the mechanisms of their toxicity are largely unknown. Here, we demonstrated that Br2 and reactive brominated species produced in the lung and released in blood reach the heart and cause acute cardiac ultrastructural damage and dysfunction in rats. Br2-induced cardiac damage was demonstrated by acute (3–24 h) increases in circulating troponin I, heart-type fatty acid-binding protein, and NH2-terminal pro-brain natriuretic peptide. Transmission electron microscopy demonstrated acute (3–24 h) cardiac contraction band necrosis, disruption of z-disks, and mitochondrial swelling and disorganization. Echocardiography and hemodynamic analysis revealed left ventricular (LV) systolic and diastolic dysfunction at 7 days. Plasma and LV tissue had increased levels of brominated fatty acids. 2-Bromohexadecanal (Br-HDA) injected into the LV cavity of a normal rat caused acute LV enlargement with extensive disruption of the sarcomeric architecture and mitochondrial damage. There was extensive infiltration of neutrophils and increased myeloperoxidase levels in the hearts of Br2- or Br2 reactant-exposed rats. Increased bromination of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and increased phosphalamban after Br2 inhalation decreased cardiac SERCA activity by 70%. SERCA inactivation was accompanied by increased Ca2+-sensitive LV calpain activity. The calpain-specific inhibitor MDL28170 administered within 1 h after exposure significantly decreased calpain activity and acute mortality. Bromine inhalation and formation of reactive brominated species caused acute cardiac injury and myocardial damage that can lead to heart failure. NEW & NOTEWORTHY The present study defines left ventricular systolic and diastolic dysfunction due to cardiac injury after bromine (Br2) inhalation. A calpain-dependent mechanism was identified as a potential mediator of cardiac ultrastructure damage. This study not only highlights the importance of monitoring acute cardiac symptoms in victims of Br2 exposure but also defines calpains as a potential target to treat Br2-induced toxicity.

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“…We developed an animal model of ARDS by exposing C57BL/6 mice to halogen gases such as chlorine (Cl 2 ) or bromine (Br 2 ). We have previously shown that exposure to Br 2 (600ppm, 30min) or Cl 2 (400ppm, 30min) causes lung pathology similar to ARDS (9,(25)(26)(27) and that this injury is mediated at least in part by halogenated lipids, formed by the interaction of halogen gases with plasmalogens on the surface of lung epithelial cells, which are released into the alveolar spaces and plasma. Recent studies have shown that these halogenated lipids are elevated in patients who have ARDS (28) secondary to sepsis and also correlate with the disease severity (28).…”

Section: Introductionmentioning

confidence: 99%

Heme Impairs Alveolar Epithelial Sodium Channels Post Toxic Gas Inhalation

Aggarwal

Lazrak

Ahmad

et al. 2020

Preprint

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Fax: (205) 934-7476; Tel: (205) 975-9673 Conflict of interest statement: The authors have declared that no conflict of interest exists.Authors Contribution: SA and IA designed and performed studies assessing RBC lysis measurements of heme and heme induced oxidative injury; AL and ZY designed and performed the ion transport experiments; JAM designed, conducted and analyzed the mass spectrometry studies; AB, DF and SM completed the necessary forms to obtain permissions from the UAB and St. Louis University IRBs to perform measurements in human samples; DAF designed and performed all measurements to assess brominated lipids in humans and mice; SA performed the modelling studies; SA, AL and SM wrote all drafts of this manuscript; SM conceived the study, designed and organized experiments, analyzed data, and inspected all primary data. ABSTRACTWe previously reported that cell-free heme (CFH) is increased in the plasma of patients with acute and chronic lung injury and causes pulmonary edema in animal model of acute respiratory distress syndrome (ARDS) post inhalation of halogen gas. However, the mechanisms by which CFH causes pulmonary edema are unclear. Herein we report for the first time the presence of CFH and chlorinated lipids (formed by the interaction of halogen gas, Cl 2 , with plasmalogens) in the plasma of patients and mice exposed to Cl 2 gas. Ex vivo incubation of red blood cells (RBC) with halogenated lipids caused oxidative damage to RBC cytoskeletal protein spectrin, resulting in hemolysis and release of CFH. A single intramuscular injection of the heme-scavenging protein hemopexin (4 µg/kg body weight) in mice, one hour post halogen exposure, reversed RBC fragility and decreased CFH levels to those of air controls. Patch clamp and short circuit current measurements revealed that CFH inhibited the activity of amiloridesensitive (ENaC) and cation sodium (Na + ) channels in mouse alveolar cells and transepithelial Na + transport across human airway cells with EC 50 of 125 nM and 500 nM, respectively. Molecular modeling identified 22 putative heme-docking sites on ENaC (energy of binding range: 86-1563 kJ/mol) with at least 2 sites within its narrow transmembrane pore, potentially capable of blocking Na + transport across the channel. In conclusion, results suggested that CFH mediated inhibition of ENaC activity may be responsible for pulmonary edema post inhalation injury.

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Role of heme in bromine‐induced lung injury

Cited by 34 publications

References 49 publications

The thioredoxin reductase inhibitor auranofin induces heme oxygenase-1 in lung epithelial cells via Nrf2-dependent mechanisms

The thioredoxin reductase inhibitor auranofin induces heme oxygenase-1 in lung epithelial cells via Nrf2-dependent mechanisms

Bromine inhalation mimics ischemia-reperfusion cardiomyocyte injury and calpain activation in rats

Heme Impairs Alveolar Epithelial Sodium Channels Post Toxic Gas Inhalation

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