Heme scavenging reduces pulmonary endoplasmic reticulum stress, fibrosis, and emphysema

Aggarwal, Saurabh; Ahmad, Israr; Lam, Adam; Carlisle, Matthew A.; Li, Changzhao; Wells, James M.; Raju, S. Vamsee; Athar, Mohammad; Rowe, Steven M.; Dransfield, Mark T.; Matalon, Sadis

doi:10.1172/jci.insight.120694

Cited by 50 publications

(78 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…*P < 0.05 vs. unexposed humans or air exposed mice; by unpaired t-test. lung injury (2)(3)(4)(5)(6)(7)(8)(9)(10). However, the mechanisms of increased RBC fragility and plasma CFH are not known.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, they also found that the effects of cell-free hemoglobin were mediated by the iron-containing heme moiety of cell-free hemoglobin, as intratracheal administration of free heme was sufficient to increase alveolar permeability in mice (20). In fact in our recent studies, we found that patients with chronic obstructive pulmonary disease (COPD) also had elevated levels of CFH (8) which correlated with the severity of the disease. In an animal model of ARDS, we found that scavenging CFH reduced pulmonary edema and improved lung function (9).…”

Section: Introductionmentioning

confidence: 90%

“…MS was performed from RBC ghosts pooled from [4][5] Heme scavenging attenuates RBC plasma membrane protein carbonylation and hemolysis: Next, we determined whether scavenging CFH would improve the integrity of RBC's plasma membrane and prevent hemolysis. We exposed C57BL/6 mice to Br 2 (600ppm) or Cl 2 (400ppm) for 30 minutes and then treated the mice with an intramuscular injection of the heme scavenging protein, hemopexin, (4mg/kg BW) 1 hour later as published earlier (8,9). RBCs were isolated from mice 1 day post exposure.…”

Section: Figure 4 Halogen Gas Exposure Increased Carbonylation Of Rbmentioning

confidence: 99%

“…We have previously shown that CFH is responsible for lung edema and lung injury post toxic gas inhalation (8)(9)(10). Therefore, to determine the mechanism of CFH-induced lung edema, in the first series of experiments, we determined whether heme inhibits active Na + transport across human bronchial epithelial cells (HBEC).…”

Section: Heme Impairs Enac Activity and Na + Transport Across Lung Epmentioning

confidence: 99%

“…Heme is an essential functional group of many proteins. However, non-encapsulated cell-free heme (CFH), a breakdown component of proteins such as hemoglobin, myoglobin, horseradish peroxidase, cytochrome b 5 , and cytochrome P450 can cause oxidative damage and impair cellular integrity (1) and is implicated in the pathogenesis of several disorders (2)(3)(4)(5)(6)(7)(8)(9)(10). CFH is an abundant source of redox-active iron capable of damaging lipid, protein, and DNA (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Heme Impairs Alveolar Epithelial Sodium Channels Post Toxic Gas Inhalation

Aggarwal

Lazrak

Ahmad

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Section: Figure 4 Halogen Gas Exposure Increased Carbonylation Of Rbmentioning

confidence: 99%

Section: Heme Impairs Enac Activity and Na + Transport Across Lung Epmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Heme Impairs Alveolar Epithelial Sodium Channels Post Toxic Gas Inhalation

Aggarwal

Lazrak

Ahmad

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Interaction Between SARS-CoV-2 and Pathogenic Bacteria

et al. 2023

View full text Add to dashboard Cite

The novel human coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which results in the coronavirus disease 2019 (COVID-19), has caused a serious threat to global public health. Therefore, many studies are performed on the causes and prevalence of this disease and the possible co-occurrence of the infection with other viral and bacterial pathogens is investigated. Respiratory infections predispose patients to co‐infections and these lead to increased disease severity and mortality. Numerous types of antibiotics have been employed for the prevention and treatment of bacterial co‐infection and secondary bacterial infections in patients with a SARS-CoV-2 infection. Although antibiotics do not directly affect SARS‐CoV‐2, viral respiratory infections often result in bacterial pneumonia. It is possible that some patients die from bacterial co‐infection rather than virus itself. Therefore, bacterial co‐infection and secondary bacterial infection are considered critical risk factors for the severity and mortality rates of COVID‐19. In this review, we will summarize the bacterial co‐infection and secondary bacterial infection in some featured respiratory viral infections, especially COVID‐19.

show abstract