Disruption of normal iron homeostasis after bronchial instillation of an iron-containing particle

1998 ◽  
Vol 274 (3) ◽  
pp. L396-L403 ◽  
Author(s):  
Andrew J. Ghio ◽  
Jacqueline D. Carter ◽  
Judy H. Richards ◽  
Luisa E. Brighton ◽  
John C. Lay ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Respiratory Tract ◽  
Transferrin Receptor ◽  
Lower Respiratory Tract ◽  
Iron Homeostasis ◽  
Middle Lobe ◽  
Metal Exposure ◽  
Enzyme Linked Immunosorbent Assay ◽  
Lobe Bronchus ◽  
Human Respiratory Tract

The atmosphere constitutes a prime vehicle for the movement and redistribution of metals. Metal exposure can be associated with an oxidative stress. We tested the hypothesis that, in response to an iron-containing particle, the human respiratory tract will demonstrate an increased expression of both lactoferrin and ferritin as the host attempts to transport and store the metal in a chemically less-reactive form and therefore diminish the oxidative stress the particle presents. Subjects ( n = 22) were instilled with 20 ml of saline and 20 ml of an iron-containing particle suspended in saline in a right middle lobe bronchus and a lingular bronchus, respectively. At either 1, 2, or 4 days after this exposure, the volunteer was lavaged for a sample of the lower respiratory tract, and concentrations ofl-ferritin, transferrin, and lactoferrin were measured by enzyme immunoassay, immunoprecipitin analysis, and enzyme-linked immunosorbent assay (ELISA), respectively. Transferrin receptor was also quantified by ELISA. The concentrations of l-ferritin in the lavage fluid of lung exposed to particles were significantly increased relative to the levels of the protein in the segment exposed to saline. Relative to saline instillation, transferrin was significantly diminished after exposure to the iron-containing particle, whereas both lactoferrin and transferrin receptor concentrations in the segment of the lung exposed to the particle were significantly elevated. We conclude that instillation of an iron-containing particle was associated with a disequilibrium in iron metabolism in the lower respiratory tract. The response included increased ferritin and lactoferrin concentrations, whereas transferrin concentrations diminished. This coordinated series of reactions by the host effects a decrease in the availability of catalytically reactive iron to likely diminish the consequent oxidative stress to the human host.

scholarly journals Variability of the Transferrin Receptor 2 Gene in AMD

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Daniel Wysokinski ◽  
Janusz Blasiak ◽  
Mariola Dorecka ◽  
Marta Kowalska ◽  
Jacek Robaszkiewicz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Risk Factors ◽  
Transferrin Receptor ◽  
Fenton Reaction ◽  
Iron Homeostasis ◽  
Critical Role ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Its Gene ◽  
Transferrin Receptor 2

Oxidative stress is a major factor in the pathogenesis of age-related macular degeneration (AMD). Iron may catalyze the Fenton reaction resulting in overproduction of reactive oxygen species. Transferrin receptor 2 plays a critical role in iron homeostasis and variability in its gene may influence oxidative stress and AMD occurrence. To verify this hypothesis we assessed the association between polymorphisms of theTFR2gene and AMD. A total of 493 AMD patients and 171 matched controls were genotyped for the two polymorphisms of theTFR2gene: c.1892C>T (rs2075674) and c.−258+123T>C (rs4434553). We also assessed the modulation of some AMD risk factors by these polymorphisms. The CC and TT genotypes of the c.1892C>T were associated with AMD occurrence but the latter only in obese patients. The other polymorphism was not associated with AMD occurrence, but the CC genotype was correlated with an increasing AMD frequency in subjects withBMI<26. The TT genotype and the T allele of this polymorphism decreased AMD occurrence in subjects above 72 years, whereas the TC genotype and the C allele increased occurrence of AMD in this group. The c.1892C>T and c.−258+123T>C polymorphisms of theTRF2gene may be associated with AMD occurrence, either directly or by modulation of risk factors.

scholarly journals Differences in the Concentrations of Small, Anionic, Antimicrobial Peptides in Bronchoalveolar Lavage Fluid and in Respiratory Epithelia of Patients with and without Cystic Fibrosis

1999 ◽  
Vol 67 (8) ◽  
pp. 4256-4259 ◽  
Author(s):  
Kim A. Brogden ◽  
Mark R. Ackermann ◽  
Paul B. McCray ◽  
Kenneth M. Huttner
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Tract ◽  
Bronchoalveolar Lavage ◽  
Alveolar Epithelium ◽  
Lavage Fluid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Human Respiratory Tract ◽  
Healthy Human ◽  
Apical Cytoplasm ◽  
Bronchiolar Epithelium

ABSTRACT Affinity-purified rabbit polyclonal (PAB96-1) and mouse monoclonal (1G9-1C2) antibodies to synthetic H-DDDDDDD-OH, an antimicrobial anionic peptide (AP) originally isolated from ovine pulmonary surfactant, were prepared and used to assess the concentrations of AP-like molecules in human respiratory tract samples. In bronchoalveolar lavage fluids, concentrations of AP-like molecules measured by enzyme-linked immunosorbent assay were significantly lower in 13 patients with cystic fibrosis (CF) (mean ± standard deviation [SD], 0.78 ± 0.46 mM) than in 34 patients without CF (1.30 ± 0.66 mM) (P = 0.01). In pulmonary tissues of three patients without CF, very little antigen was stained in the apical cytoplasm of the bronchial and bronchiolar epithelium yet robust staining was seen in the alveolar epithelium. In pulmonary tissues of three patients with CF, robust staining of antigen was seen in the apical cytoplasm of the bronchial and bronchiolar epithelium yet no staining was seen in the alveolar epithelium. These results show that AP-like molecules are present in healthy human respiratory tract samples and differ in concentration and location of expression in patients with and without CF.

Oxidative Stress Response of PM2.5 and Mixed Toxic Gases to Rat Trachea and Lung Tissue

2021 ◽  
Author(s):  
Shouqin Wang ◽  
Jia Xu ◽  
Biao Yang ◽  
Dongmei Chen ◽  
Hui Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Respiratory Tract ◽  
Lung Tissue ◽  
Normal Structure ◽  
Time Dependent ◽  
Enzyme Linked Immunosorbent Assay ◽  
Electron Microscopic ◽  
Toxic Gases ◽  
Toxic Gas ◽  
Rat Trachea

Abstract Background：We performed this study to explore the inflammation and oxidative stress responses of rat trachea and lung caused by PM2.5 and mixed toxic gas.Materials and methods：Eighty-four Wistar rats were randomly assigned to receive exposure to PM2.5 and toxic gases containing carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2) or saline. Microflora in rat respiratory tract were investigated through testing secretion taken from posterior pharyngeal wall on Day 1, 7 and 30. Trachea and lung tissues were processed for scanning electron microscopic (SEM) and transmission electron microscopic (TEM) examinations. Cytokines in rat bronchoalveolar lavage fluid (BALF), serum and lung tissues were analyzed via enzyme-linked immunosorbent assay and real-time quantitative PCR.Results：Eight aerobes and seven anaerobes were firstly detected after exposure (p<0.01, respectively). Most of them are the pathogenic bacteria or opportunistic pathogen. SEM and TEM observations suggested that both normal structure of trachea and lung tissue were injured after exposure to PM2.5 with mixed toxic gas and the injure degree was concentration- and time-dependent. Interleukin 4 (IL-4), interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) expression in the BALF and lung tissue markedly increased on Day 1 and 7 (p<0.01, respectively). Interferon γ (IFN-γ) did not show significant change after exposure. On Day 30, all the detected cytokines decreased and even disappeared. All detected cytokines in the serum had no significant difference before and after exposure (p>0.05, respectively).Conclusion：PM2.5 with mixed toxic gas can lead to dysbacteriosis in respiratory tract and destroy the normal structure of trachea and lung tissue. The injure degree was concentration- and time-dependent. Local inflammatory response instead of systemic reaction may be predominant in the response of rat respiratory tract to PM2.5 with mixed toxic gas.

Transferrin Receptor 1 Up-Regulation Plays a Role in Iron Accumulation in a Murine Model of Sideroblastic Anemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3585-3585
Author(s):  
Florent M. Martin ◽  
Timothy J. Gilmartin ◽  
Gabriela Bydlon ◽  
Megan L. Welsh ◽  
Jeffrey S. Friedman
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Stem Cells ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Oxygen Species ◽  
Wild Type ◽  
Sideroblastic Anemia ◽  
Hematopoietic Stem ◽  
Transferrin Receptor 1

Abstract Manganese superoxide dismutase (SOD2) detoxifies superoxide anion radicals generated by mitochondrial respiration (Weisiger and Fridovich, J. Biol. Chem. 1973). While SOD2-deficiency is lethal, SOD2-deficient (SOD2−/−) hematopoietic stem cells can rescue lethally irradiated wild-type mice. SOD2−/− hematopoietic chimeras show a persistent hemolytic anemia similar to human sideroblastic anemia (Friedman et al. J. Exp. Med. 2001). SOD2−/− erythroid progenitor cells have increased mitochondrial mass, and reticulocytes show mitochondrial iron deposition. Mature RBC show abundant siderotic granules, evidence of a defect in iron incorporation into heme, and shortened lifespan. SOD2−/− progenitors and mature RBC show both enhanced reactive oxygen species production and protein oxidative damage (Friedman et al. Blood 2004; Martin et al. Submitted). To define early events in the pathogenesis of the SOD2-deficiency anemia and, in particular to identify genes involved in the response of erythroid progenitors to oxidative stress, we compared gene expression of sorted TER-119+ CD71+ erythroblasts from SOD2−/−versus wild-type hematopoietic stem cells recipients. Using cDNA microarrays and class comparison analysis, we identified 600 transcripts as significantly discriminant between genotypes. Analysis showed that eleven transcripts encoding different subunits of the mitochondrial oxidative phosphorylation, ATP synthase, and TCA cycle were down-regulated in SOD2−/− erythroblasts. Previous work showed similar results at the protein level in SOD2−/− RBC (Friedman et al. Blood 2004) and at the activity level in specific tissues of SOD2−/− neonates prior to death (Melov et al. PNAS 1999). One interpretation is that SOD2−/− erythroblasts show metabolic decline. Of interest, a single transcript involved in iron homeostasis, Trfr, was found to be expressed at twice the levels found in wild-type erythroblasts (p&lt;0.0007, parametric p value). Trfr encodes transferrin receptor 1; two-fold up-regulation of transferrin receptor 1 was also shown at the protein level by flow cytometry analysis of SOD2−/− erythroblasts (p&lt;0.0001, unpaired two-tailed t-test). Transferrin receptor 1 is the cellular gatekeeper for iron uptake whose genetic inactivation induces abnormal erythropoiesis and iron homeostasis (Levy et al. Nat. Genet. 1999). The stability of the Trfr transcript is highly regulated by iron regulatory proteins (IRPs), that are known to be controlled by numerous effectors including reactive oxygen species (Hentze et al. Cell 2004, for review). We focus our current work on investigating, in vitro and in vivo, the role that up-regulation of transferrin receptor 1, likely through oxidative stress-mediated IRPs activity regulation, plays in iron overload in our SOD2-deficiency model. Taken together, our findings raise the possibility that increased iron delivery may be sufficient to cause sideroblastic anemia or may contribute to a self-reinforcing cycle where oxidative stress favors increased iron, and increased iron results in enhanced oxidative damage.

scholarly journals Cysteine Oxidation Regulates the RNA-Binding Activity of Iron Regulatory Protein 2

2009 ◽  
Vol 29 (8) ◽  
pp. 2219-2229 ◽  
Author(s):  
Kimberly B. Zumbrennen ◽  
Michelle L. Wallander ◽  
S. Joshua Romney ◽  
Elizabeth A. Leibold
Keyword(s):  
Oxidative Stress ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Rna Binding ◽  
Regulatory Protein ◽  
Binding Activity ◽  
Structural Basis ◽  
Iron Regulatory Protein ◽  
Transferrin Receptor 1 ◽  
Binding Cleft

ABSTRACT Iron regulatory protein 2 (IRP2) is an RNA-binding protein that regulates the posttranscriptional expression of proteins required for iron homeostasis such as ferritin and transferrin receptor 1. IRP2 RNA-binding activity is primarily regulated by iron-mediated proteasomal degradation, but studies have suggested that IRP2 RNA binding is also regulated by thiol oxidation. We generated a model of IRP2 bound to RNA and found that two cysteines (C512 and C516) are predicted to lie in the RNA-binding cleft. Site-directed mutagenesis and thiol modification show that, while IRP2 C512 and C516 do not directly interact with RNA, both cysteines are located within the RNA-binding cleft and must be unmodified/reduced for IRP2-RNA interactions. Oxidative stress induced by cellular glucose deprivation reduces the RNA-binding activity of IRP2 but not IRP2-C512S or IRP2-C516S, consistent with the formation of a disulfide bond between IRP2 C512 and C516 during oxidative stress. Decreased IRP2 RNA binding is correlated with reduced transferrin receptor 1 mRNA abundance. These studies provide insight into the structural basis for IRP2-RNA interactions and reveal an iron-independent mechanism for regulating iron homeostasis through the redox regulation of IRP2 cysteines.

scholarly journals Patients with Community Acquired Pneumonia Exhibit Depleted Vitamin C Status and Elevated Oxidative Stress

2020 ◽  
Author(s):  
Anitra C. Carr ◽  
Emma Spencer ◽  
Liane Dixon ◽  
Steve Chambers
Keyword(s):  
Oxidative Stress ◽  
Vitamin C ◽  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Protein Carbonyl ◽  
Community Acquired Pneumonia ◽  
Healthy Controls ◽  
Elevated Protein ◽  
Vitamin C Supplementation ◽  
Tract Infections

Pneumonia is a severe lower respiratory tract infection that is a common complication and a major cause of mortality of the vitamin C-deficiency disease scurvy. This suggests an important link between vitamin C status and lower respiratory tract infections. Due to the paucity of information on the vitamin C status of patients with pneumonia, we assessed the vitamin C status of 50 patients with community-acquired pneumonia and compared these with 50 healthy community controls. The pneumonia cohort comprised 44 patients recruited through the Acute Medical Assessment Unit (AMAU) and 6 patients recruited through the intensive care unit (ICU); mean age 68 &plusmn; 17 years, 54% male. Clinical, microbiological and haematological parameters were recorded. Blood samples were tested for vitamin C status using HPLC with electrochemical detection and protein carbonyl concentrations, a marker of oxidative stress, using ELISA. Patients with pneumonia had depleted vitamin C status compared with healthy controls (23 &plusmn; 14 &micro;mol/L vs 56 &plusmn; 24 &micro;mol/L, P &lt;0.001). The more severe patients in the ICU had significantly lower vitamin C status than those recruited through AMAU (11 &plusmn; 3 &micro;mol/L vs 24 &plusmn; 14 &micro;mol/L, P = 0.02). The total pneumonia cohort comprised 62% with hypovitaminosis C and 22% with deficiency, compared with only 8% hypovitaminosis C and no cases of deficiency in the healthy controls. The pneumonia cohort also exhibited significantly elevated protein carbonyl concentrations compared with the healthy controls (P &lt; 0.001), indicating enhanced oxidative stress in the patients. We were able to collect subsequent samples form 28% of the cohort (mean 2.7 &plusmn; 1.7 days; range 1-7 days). These showed no significant differences in vitamin C status or protein carbonyl concentrations compared with baseline values (P = 0.6). Overall, the depleted vitamin C status and elevated oxidative stress observed in the patients with pneumonia indicates an enhanced requirement for the vitamin during their illness. Due to the important roles that vitamin C plays in the immune system, low vitamin C status is possibly both a cause and a consequence of the disease. Therefore, these patients would likely benefit from additional vitamin C supplementation to restore their blood and tissue levels to optimal. This may decrease oxidative stress and aid in their recovery.

scholarly journals Patients with Community Acquired Pneumonia Exhibit Depleted Vitamin C Status and Elevated Oxidative Stress

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1318 ◽  
Author(s):  
Anitra C. Carr ◽  
Emma Spencer ◽  
Liane Dixon ◽  
Stephen T. Chambers
Keyword(s):  
Oxidative Stress ◽  
Vitamin C ◽  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Hematological Parameters ◽  
Protein Carbonyl ◽  
Community Acquired Pneumonia ◽  
Healthy Controls ◽  
Vitamin C Supplementation ◽  
Tract Infections

Pneumonia is a severe lower respiratory tract infection that is a common complication and a major cause of mortality of the vitamin C-deficiency disease scurvy. This suggests an important link between vitamin C status and lower respiratory tract infections. Due to the paucity of information on the vitamin C status of patients with pneumonia, we assessed the vitamin C status of 50 patients with community-acquired pneumonia and compared these with 50 healthy community controls. The pneumonia cohort comprised 44 patients recruited through the Acute Medical Assessment Unit (AMAU) and 6 patients recruited through the Intensive Care Unit (ICU); mean age 68 ± 17 years, 54% male. Clinical, microbiological and hematological parameters were recorded. Blood samples were tested for vitamin C status using HPLC with electrochemical detection and protein carbonyl concentrations, an established marker of oxidative stress, using ELISA. Patients with pneumonia had depleted vitamin C status compared with healthy controls (23 ± 14 µmol/L vs. 56 ± 24 µmol/L, p < 0.001). The more severe patients in the ICU had significantly lower vitamin C status than those recruited through AMAU (11 ± 3 µmol/L vs. 24 ± 14 µmol/L, p = 0.02). The pneumonia cohort comprised 62% with hypovitaminosis C and 22% with deficiency, compared with only 8% hypovitaminosis C and no cases of deficiency in the healthy controls. The pneumonia cohort also exhibited significantly elevated protein carbonyl concentrations compared with the healthy controls (p < 0.001), indicating enhanced oxidative stress in the patients. We were able to collect subsequent samples from 28% of the cohort (mean 2.7 ± 1.7 days; range 1–7 days). These showed no significant differences in vitamin C status or protein carbonyl concentrations compared with baseline values (p = 0.6). Overall, the depleted vitamin C status and elevated oxidative stress observed in the patients with pneumonia indicates an enhanced requirement for the vitamin during their illness. Therefore, these patients would likely benefit from additional vitamin C supplementation to restore their blood and tissue levels to optimal. This may decrease excessive oxidative stress and aid in their recovery.

scholarly journals Characteristics and Antibiotic Resistance of Haemophilus influenzae in Children with Lower Respiratory Tract Infection in Chengdu, China

2021 ◽  
Vol 14 (2) ◽  
Author(s):  
Qin Wang ◽  
Cheng-Gui Liu ◽  
Jian Xu ◽  
Qin Zhang ◽  
Chong-Hui Zhao ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Tract Infection ◽  
Respiratory Tract ◽  
Haemophilus Influenzae ◽  
Respiratory Tract Infection ◽  
Lower Respiratory Tract Infection ◽  
Lower Respiratory Tract ◽  
Detection Rate ◽  
Human Respiratory Tract ◽  
Positive Rate

Background: Haemophilus influenzae is an opportunistic pathogen of the human respiratory tract. Haemophilus influenzae can cause not only respiratory tract infection in children but also otitis media, epiglottitis and sinusitis. With the widespread use of antibiotics, the positive rate of β-lactamase in H. influenzae is increasing, and the rate of antimicrobial resistance is also increasing, which increases the difficulty of clinical treatment. Objectives: To study the infection characteristics of patients and the antibiotic resistance of H. influenzae in lower respiratory tract samples of children in Chengdu, so as to provide a reference for its clinical diagnosis and the rational use of antibiotics. Methods: Sputum samples of 15891 children aged 0-14 years with lower respiratory tract infection were collected. Haemophilus influenzae was cultured and identified, its drug susceptibility tested, and the results determined according to the guidelines of CLSI 2020. Results: A total of 15891 clinical isolate strains in sputum were detected for drug sensitivity from December 2018 to January 2020, of which 5488 were H. influenzae, accounting for 34.54% (5488/15891). The sex of children infected with H. influenzae was not skewed (P > 0.05). The detection rate of H. influenzae was the highest in children aged 7 - 11 months, and the lowest was in the age group ≤ 28 d. The detection rate was the highest in spring and the lowest in autumn. The positive rate of β-lactamase was 92.0%, the resistance rate to ampicillin was 92.0%, the sensitivity to amoxicillin/clavulanate was 70.2%, and the sensitivity to cefotaxime, ofloxacin, tetracycline, chloramphenicol, and rifampicin was more than 90.0%. Conclusions: Children aged 7 months to 14 years were generally susceptible to H. influenzae in spring, and the positive rate of β-lactamase was high. Doctors should refer to the infection characteristics and drug resistance of H. influenzae and choose antibiotics correctly to better control the infection.

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