Publications by authors named "Sadis Matalon"

167 Publications

Noninvasive Assessment of Right Ventricle Function and Pulmonary Artery Pressure Using Transthoracic Echocardiography in Women With Pre-Eclampsia: An Exploratory Study.

Cureus 2021 Feb 18;13(2):e13419. Epub 2021 Feb 18.

Pediatrics, University of Alabama at Birmingham, Birmingham, USA.

Background and objective Pre-eclampsia (PEC) is associated with the release of anti-angiogenic factors that are incriminated in raising systemic and pulmonary vascular resistance (PVR). Compared to the left heart and systemic circulation, much less attention has been paid to the right heart and pulmonary circulation in patients with PEC. We used transthoracic echocardiography (TTE) to estimate pulmonary artery (PA) pressure and right ventricular (RV) function in women with PEC. Materials and methods We conducted a case-control study at a tertiary care academic center. Ten early PEC (<34-week gestation) and nine late PEC (≥34-week gestation) patients with 11 early and 10 late gestational age-matched controls were enrolled. Two-dimensional TTE was performed on all patients. The estimated mean PA pressure (eMPAP) was calculated based on PA acceleration time (PAAT). PVR was estimated from eMPAP and RV cardiac output (RV CO). RV myocardial performance index (RV MPI), tricuspid annular plane systolic excursion (TAPSE), tissue tricuspid annular displacement (TTAD), and lateral tricuspid annular tissue peak systolic velocity (S') were measured. Results Compared to early controls, in early PEC, the eMPAP and estimated PVR (ePVR) were elevated, PAAT was reduced, RV MPI was increased, TTAD was reduced, and TAPSE and TV S' were unchanged. Compared to late controls, in late PEC, the eMPAP and ePVR were elevated, PAAT was reduced, and RV MPI was increased, while TAPSE, TTAD, and TV S' were unchanged. Conclusions In a sample of women with PEC, early PEC was found to be associated with increased eMPAP and ePVR and subclinical decrement of RV function as assessed by TTE. TTE may be a useful noninvasive screening tool for early detection of pulmonary hypertension and RV dysfunction in PEC. An adequately powered longitudinal study is needed to determine the implications of these findings on long-term outcomes.
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http://dx.doi.org/10.7759/cureus.13419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980723PMC
February 2021

: THE PAST, THE PRESENT, AND THE FUTURE.

Physiol Rev 2021 Apr 14;101(2):733-738. Epub 2021 Jan 14.

Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri.

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http://dx.doi.org/10.1152/physrev.00001.2021DOI Listing
April 2021

Korean Red Ginseng aqueous extract improves markers of mucociliary clearance by stimulating chloride secretion.

J Ginseng Res 2021 Jan 13;45(1):66-74. Epub 2019 Sep 13.

Department of Otolaryngology Head & Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States.

Background: Abnormal chloride (Cl) transport has a detrimental impact on mucociliary clearance in both cystic fibrosis (CF) and non-CF chronic rhinosinusitis. Ginseng is a medicinal plant noted to have anti-inflammatory and antimicrobial properties. The present study aims to assess the capability of red ginseng aqueous extract (RGAE) to promote transepithelial Cl secretion in nasal epithelium.

Methods: Primary murine nasal septal epithelial (MNSE) [wild-type (WT) and transgenic CFTR], fisher-rat-thyroid (FRT) cells expressing human WT CFTR, and TMEM16A-expressing human embryonic kidney cultures were utilized for the present experiments. Ciliary beat frequency (CBF) and airway surface liquid (ASL) depth measurements were performed using micro-optical coherence tomography (μOCT). Mechanisms underlying transepithelial Cl transport were determined using pharmacologic manipulation in Ussing chambers and whole-cell patch clamp analysis.

Results: RGAE (at 30μg/mL of ginsenosides) significantly increased Cl transport [measured as change in short-circuit current (ΔI = μA/cm)] when compared with control in WT and CFTR MNSE (WT vs control = 49.8±2.6 vs 0.1+/-0.2, CFTR = 33.5±1.5 vs 0.2±0.3, p < 0.0001). In FRT cells, the CFTR-mediated ΔI attributed to RGAE was small (6.8 ± 2.5 vs control, 0.03 ± 0.01, p < 0.05). In patch clamp, TMEM16A-mediated currents were markedly improved with co-administration of RGAE and uridine 5-triphosphate (8406.3 +/- 807.7 pA) over uridine 5-triphosphate (3524.1 +/- 292.4 pA) or RGAE alone (465.2 +/- 90.7 pA) (p < 0.0001). ASL and CBF were significantly greater with RGAE (6.2+/-0.3 m vs control, 3.9+/-0.09 m; 10.4+/-0.3 Hz vs control, 7.3 ± 0.2 Hz;  < 0.0001) in MNSE.

Conclusion: RGAE augments ASL depth and CBF by stimulating Cl secretion through CaCC, which suggests therapeutic potential in both CF and non-CF chronic rhinosinusitis.
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http://dx.doi.org/10.1016/j.jgr.2019.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790903PMC
January 2021

The chemokine CX3CL1/fractalkine regulates immunopathogenesis during fungal-associated allergic airway inflammation.

Am J Physiol Lung Cell Mol Physiol 2021 03 16;320(3):L393-L404. Epub 2020 Dec 16.

Department of Microbiology and Immunology, Tulane University, New Orleans, Louisiana.

Individuals that present with difficult-to-control asthma and sensitivity to one or more fungal species are categorized as a subset of severe asthma patients belonging to a group herein referred to as severe asthma with fungal sensitization (SAFS). We have previously reported the identification of numerous cytokines and chemokines that were elevated in human asthmatics that were sensitized to fungi vs. nonfungal sensitized asthmatics. Here, we show that the unique chemokine CX3CL1 (fractalkine) is elevated in both bronchoalveolar lavage fluid and sputum from human asthmatics sensitized to fungi, implicating an association with CX3CL1 in fungal asthma severity. In an experimental model of fungal-associated allergic airway inflammation, we demonstrate that the absence of CX3CR1 signaling unexpectedly resulted in a profound impairment in lung function. Histological assessment of lung tissue revealed an unrestricted inflammatory response that was subsequently characterized by enhanced levels of neutrophils, eosinophils, and inflammatory monocytes. Neutrophilic inflammation correlated with elevated IL-17A, proinflammatory cytokines (TNF-α, IL-1α, and IL-1β), neutrophil survival factors (granulocyte colony-stimulating factor), and neutrophil-targeting chemokines (CCL3 and CCL4). Eosinophilia correlated with elevated type 2 responses (IL-5 and IL-13) whereas inflammatory monocyte levels correlated with elevated type 1 responses (IFN-γ and CXCL9) and survival factors (macrophage colony-stimulating factor). Despite enhanced inflammatory responses, the immunoregulatory cytokine IL-10 and the natural inhibitor of IL-1 signaling, IL-1RA, were significantly elevated rather than impaired. Regulatory T-cell levels were unchanged, as were levels of the anti-inflammatory cytokines IL-35 and IL-38. Taken together, the CX3CL1/CX3CR1 axis preserves lung function during fungal-associated allergic airway inflammation through a nonclassical immunoregulatory mechanism.
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http://dx.doi.org/10.1152/ajplung.00376.2020DOI Listing
March 2021

Heme attenuates beta-endorphin levels in leukocytes of HIV positive individuals with chronic widespread pain.

Redox Biol 2020 09 13;36:101684. Epub 2020 Aug 13.

Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, USA.

The prevalence of chronic widespread pain (CWP) in people with HIV is high, yet the underlying mechanisms are elusive. Leukocytes synthesize the endogenous opioid, β-endorphin, within their endoplasmic reticulum (ER). When released into plasma, β-endorphin dampens nociception by binding to opioid receptors on sensory neurons. We hypothesized that the heme-dependent redox signaling induces ER stress, which attenuates leukocyte β-endorphins levels/release, thereby increasing pain sensitivity in people with HIV. Results demonstrated that HIV positive individuals with CWP had increased plasma methemoglobin, erythrocytes membrane oxidation, hemolysis, and low plasma heme scavenging enzyme, hemopexin, compared to people with HIV without CWP and HIV-negative individuals with or without pain. In addition, the leukocytes from people with HIV with CWP had attenuated levels of the heme metabolizing enzyme, heme oxygenase-1, which metabolizes free heme to carbon-monoxide and biliverdin. These individuals also had elevated ER stress, and low β-endorphin in leukocytes. In vitro, heme exposure or heme oxygenase-1 deletion, decreased β-endorphins in murine monocytes/macrophages. Treating cells with a carbon-monoxide donor or an ER stress inhibitor, increased β-endorphins. To mimic hemolytic effects in a preclinical model, C57BL/6 mice were injected with phenylhydrazine hydrochloride (PHZ). PHZ increased cell-free heme and ER stress, decreased leukocyte β-endorphin levels and hindpaw mechanical sensitivity thresholds. Treatment of PHZ-injected mice with hemopexin blocked these effects, suggesting that heme-induced ER stress and a subsequent decrease in leukocyte β-endorphin is responsible for hypersensitivity in people with HIV.
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http://dx.doi.org/10.1016/j.redox.2020.101684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451624PMC
September 2020

SARS-CoV-2 may regulate cellular responses through depletion of specific host miRNAs.

Am J Physiol Lung Cell Mol Physiol 2020 09 5;319(3):L444-L455. Epub 2020 Aug 5.

Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.

Cold viruses have generally been considered fairly innocuous until the appearance of the severe acute respiratory coronavirus 2 (SARS-CoV-2) in 2019, which caused the coronavirus disease 2019 (COVID-19) global pandemic. Two previous viruses foreshadowed that a coronavirus could potentially have devastating consequences in 2002 [severe acute respiratory coronavirus (SARS-CoV)] and in 2012 [Middle East respiratory syndrome coronavirus (MERS-CoV)]. The question that arises is why these viruses are so different from the relatively harmless cold viruses. On the basis of an analysis of the current literature and using bioinformatic approaches, we examined the potential human miRNA interactions with the SARS-CoV-2's genome and compared the miRNA target sites in seven coronavirus genomes that include SARS-CoV-2, MERS-CoV, SARS-CoV, and four nonpathogenic coronaviruses. Here, we discuss the possibility that pathogenic human coronaviruses, including SARS-CoV-2, could modulate host miRNA levels by acting as miRNA sponges to facilitate viral replication and/or to avoid immune responses.
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http://dx.doi.org/10.1152/ajplung.00252.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473886PMC
September 2020

Halogen exposure injury in the developing lung.

Ann N Y Acad Sci 2020 11 1;1480(1):30-43. Epub 2020 Aug 1.

Division of Neonatology, Department of Pediatrics, the University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.

Owing to a high-volume industrial usage of the halogens chlorine (Cl ) and bromine (Br ), they are stored and transported in abundance, creating a risk for accidental or malicious release to human populations. Despite extensive efforts to understand the mechanisms of toxicity upon halogen exposure and to develop specific treatments that could be used to treat exposed individuals or large populations, until recently, there has been little to no effort to determine whether there are specific features and or the mechanisms of halogen exposure injury in newborns or children. We established a model of neonatal halogen exposure and published our initial findings. In this review, we aim to contrast and compare the findings in neonatal mice exposed to Br with the findings published on adult mice exposed to Br and the neonatal murine models of bronchopulmonary dysplasia. Despite remarkable similarities across these models in overall alveolar architecture, there are distinct functional and apparent mechanistic differences that are characteristic of each model. Understanding the mechanistic and functional features that are characteristic of the injury process in neonatal mice exposed to halogens will allow us to develop countermeasures that are appropriate for, and effective in, this unique population.
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http://dx.doi.org/10.1111/nyas.14445DOI Listing
November 2020

Cyclosporine: an old weapon in the fight against coronaviruses.

Eur Respir J 2020 11 26;56(5). Epub 2020 Nov 26.

Depts of Anesthesiology and Perioperative Medicine, Division of Translational and Molecular Biomedicine and Pulmonary Injury and Repair Center, University of Alabama at Birmingham, School of Medicine, Birmingham, AL, USA.

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http://dx.doi.org/10.1183/13993003.02484-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397953PMC
November 2020

Vascular permeability disruption explored in the proteomes of mouse lungs and human microvascular cells following acute bromine exposure.

Am J Physiol Lung Cell Mol Physiol 2020 08 24;319(2):L337-L359. Epub 2020 Jun 24.

Division of Molecular and Translational Biomedicine, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.

Bromine (Br) is an organohalide found in nature and is integral to many manufacturing processes. Br is toxic to living organisms, and high concentrations can prove fatal. To meet industrial demand, large amounts of purified Br are produced, transported, and stored worldwide, providing a multitude of interfaces for potential human exposure through either accidents or terrorism. To identify the key mechanisms associated with acute Br exposure, we have surveyed the lung proteomes of C57BL/6 male mice and human lung-derived microvascular endothelial cells (HMECs) at 24 h following exposure to Br in concentrations likely to be encountered in the vicinity of industrial accidents. Global discovery proteomics applications combined with systems biology analysis identified robust and highly significant changes in proteins associated with three biological processes: ) exosome secretion, ) inflammation, and ) vascular permeability. We focused on the latter, conducting physiological studies on isolated perfused lungs harvested from mice 24 h after Br exposure. These experiments revealed significant increases in the filtration coefficient () indicating increased permeability of the pulmonary vasculature. Similarly, confluent monolayers of Br and Br-lipid-treated HMECs exhibited differential levels of zona occludens-1 that were found to be dissociated from cell wall localization, an increase in phosphorylation and internalization of E-cadherin, as well as increased actin stress fiber formation, all of which are consistent with increased permeability. Taken as a whole, our discovery proteomics and systems analysis workflow, combined with physiological measurements of permeability, revealed both profound and novel biological changes that contribute to our current understanding of Br toxicity.
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http://dx.doi.org/10.1152/ajplung.00196.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473936PMC
August 2020

Hyaluronan and halogen-induced airway hyperresponsiveness and lung injury.

Ann N Y Acad Sci 2020 11 23;1479(1):29-43. Epub 2020 Jun 23.

Division of Molecular and Translational Biomedicine, the University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.

Chlorine (Cl ) and bromine (Br ) are produced in large quantities throughout the world and used in the industry and the sanitation of water. These halogens can pose a significant threat to public health when released into the atmosphere during transportation and industrial accidents, or as acts of terrorism. In this review, we discuss the evidence showing that the activity of Cl and Br , and of products formed by their interaction with biomolecules, fragment high-molecular-weight hyaluronan (HMW-HA), a key component of the interstitial space and present in epithelial cells, to form proinflammatory, low-molecular-weight hyaluronan fragments that increase intracellular calcium (Ca ) and activate RAS homolog family member A (RhoA) in airway smooth muscle and epithelial and microvascular cells. These changes result in airway hyperresponsiveness (AHR) to methacholine and increase epithelial and microvascular permeability. The increase in intracellular Ca is the result of the activation of the calcium-sensing receptor by Cl , Br , and their by-products. Posthalogen administration of a commercially available form of HMW-HA to mice and to airway cells in vitro reverses the increase of Ca and the activation of RhoA, and restores AHR to near-normal levels of airway function. These data have established the potential of HMW-HA to be a countermeasure against Cl and Br toxicity.
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http://dx.doi.org/10.1111/nyas.14415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680259PMC
November 2020

Reactive species generated by heme impair alveolar epithelial sodium channel function in acute respiratory distress syndrome.

Redox Biol 2020 09 1;36:101592. Epub 2020 Jun 1.

Division of Molecular and Translational Biomedicine, USA; Pulmonary Injury and Repair Center, USA; Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35205-3703, USA. Electronic address:

We previously reported that the highly reactive cell-free heme (CFH) is increased in the plasma of patients with 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 that CFH and chlorinated lipids (formed by the interaction of halogen gas, Cl, with plasmalogens) are increased in the plasma of patients exposed to Cl 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. Patch clamp and short circuit current measurements revealed that CFH inhibited the activity of amiloride-sensitive epithelial Na channel (ENaC) and cation sodium (Na) channels in mouse alveolar cells and trans-epithelial Na transport across human airway cells with EC 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. A single intramuscular injection of the heme-scavenging protein, hemopexin (4 μg/kg body weight), one hour post halogen gas exposure, decreased plasma CFH and improved lung ENaC activity in mice. In conclusion, results suggested that CFH mediated inhibition of ENaC activity may be responsible for pulmonary edema post inhalation injury.
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http://dx.doi.org/10.1016/j.redox.2020.101592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276446PMC
September 2020

Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility.

Physiol Rev 2020 07 27;100(3):1065-1075. Epub 2020 Mar 27.

Department of Cellular and Molecular Biology, University of Texas Health Science Centre at Tyler, Tyler, Texas; Texas Lung Injury Institute, University of Texas Health Science Centre at Tyler, Tyler, Texas; Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and Department of Medicine and Anesthesia, University of California San Francisco, San Francisco, California.

Patients with hypertension, diabetes, coronary heart disease, cerebrovascular illness, chronic obstructive pulmonary disease, and kidney dysfunction have worse clinical outcomes when infected with SARS-CoV-2, for unknown reasons. The purpose of this review is to summarize the evidence for the existence of elevated plasmin(ogen) in COVID-19 patients with these comorbid conditions. Plasmin, and other proteases, may cleave a newly inserted furin site in the S protein of SARS-CoV-2, extracellularly, which increases its infectivity and virulence. Hyperfibrinolysis associated with plasmin leads to elevated D-dimer in severe patients. The plasmin(ogen) system may prove a promising therapeutic target for combating COVID-19.
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http://dx.doi.org/10.1152/physrev.00013.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191627PMC
July 2020

Halogen gas exposure: toxic effects on the parturient.

Toxicol Mech Methods 2021 May 30;31(4):272-287. Epub 2020 Mar 30.

Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

The elemental halogens include chlorine, bromine, and phosgene. Halogen gas can be directly weaponized and employed in warfare or terrorism. Industrial stockpiles or halogen transport can provide targets for terrorist attack as well as an origin for accidental release creating a risk for potential mass-casualty incidents. Pregnant and post-partum women represent a substantial and vulnerable subset of the population who may be at particular risk during an attack or accidental exposure. We review the effects of halogen exposure on the parturient with a focus on bromine toxicity. Bromine is the most extensively studied agent in the context of pregnancy and to-date murine models form the basis for the majority of current knowledge. Pregnancy potentiates the acute lung injury after halogen exposure. In addition, halogen exposure precipitates a preeclamptic-like syndrome in mice. This phenotype is characterized by systemic and pulmonary hypertension, endothelial dysfunction, decreased cardiac output, placental injury and fetal growth restriction. This constellation contributes to increased maternal and fetal mortality observed after bromine exposure. Angiogenic imbalance is noted with overexpression of the soluble fms-like tyrosine kinase-1 (sFlt-1) form of the vascular endothelial growth factor receptor 1 reminiscent of human preeclampsia. Additional research is needed to further explore the effect of halogen gas exposure in pregnancy and to develop therapeutic interventions to mitigate risk to this unique population.
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http://dx.doi.org/10.1080/15376516.2020.1736702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547547PMC
May 2021

Vascular Endothelial Growth Factor-121 Administration Mitigates Halogen Inhalation-Induced Pulmonary Injury and Fetal Growth Restriction in Pregnant Mice.

J Am Heart Assoc 2020 02 3;9(3):e013238. Epub 2020 Feb 3.

Division of Molecular and Translational Biomedicine Department of Anesthesiology and Perioperative Medicine University of Alabama at Birmingham Birmingham AL USA.

Background Circulating levels of sFLT-1 (soluble fms-like tyrosine kinase 1), the extracellular domain of vascular endothelial growth factor (VEGF) receptor 1, and its ratio to levels of placental growth factor are markers of the occurrence and severity of preeclampsia. Methods and Results C57BL/6 pregnant mice on embryonic day 14.5 (E14.5), male, and non-pregnant female mice were exposed to air or to Br at 600 ppm for 30 minutes and were treated with vehicle or with VEGF-121 (100 μg/kg, subcutaneously) daily, starting 48 hours post-exposure. Plasma, bronchoalveolar lavage fluid, lungs, fetuses, and placentas were collected 120 hours post-exposure. In Br-exposed pregnant mice, there was a time-dependent and significant increase in plasma levels of sFLT-1 which correlated with increases in mouse lung wet/dry weights and bronchoalveolar lavage fluid protein content. Supplementation of exogenous VEGF-121 improved survival and weight gain, reduced lung wet/dry weights, decreased bronchoalveolar lavage fluid protein levels, enhanced placental development, and improved fetal growth in pregnant mice exposed to Br. Exogenous VEGF-121 administration had no effect in non-pregnant mice. Conclusions These results implicate inhibition of VEGF signaling driven by sFLT-1 overexpression as a mechanism of pregnancy-specific injury leading to lung edema, maternal mortality, and fetal growth restriction after bromine gas exposure.
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http://dx.doi.org/10.1161/JAHA.119.013238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033856PMC
February 2020

Upregulation of airway smooth muscle calcium-sensing receptor by low-molecular-weight hyaluronan.

Am J Physiol Lung Cell Mol Physiol 2020 03 8;318(3):L459-L471. Epub 2020 Jan 8.

Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine & Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, Alabama.

We investigated the mechanisms involved in the development of airway hyperresponsiveness (AHR) following exposure of mice to halogens. Male mice (C57BL/6; 20-25 g) exposed to either bromine (Br) or Cl (600 or 400 ppm, respectively, for 30 min) developed AHR 24 h after exposure. Nifedipine (5 mg/kg body wt; an L-type calcium channel blocker), administered subcutaneously after Br or Cl exposure, produced higher AHR compared with Br or Cl alone. In contrast, diltiazem (5 mg/kg body wt; a nondihydropyridine L-type calcium channel blocker) decreased AHR to control (air) values. Exposure of immortalized human airway smooth muscle cells (hASMC) to Br resulted in membrane potential depolarization ( Air: 62 ± 3 mV; 3 h post Br:-45 ± 5 mV; means ± 1 SE; < 0.001), increased intracellular [Ca], and increased expression of the calcium-sensing receptor (Ca-SR) protein. Treatment of hASMC with a siRNA against Ca-SR significantly inhibited the Br and nifedipine-induced depolarization and [Ca] increase. Intranasal administration of an antagonist to Ca-SR in mice postexposure to Br reversed the effects of Br and nifedipine on AHR. Incubation of hASMC with low-molecular-weight hyaluronan (LMW-HA), generated by exposing high-molecular-weight hyaluronan (HMW-HA) to Br, caused depolarization, [Ca] increase, and Ca-SR expression to a similar extent as exposure to Br and Cl. The addition of HMW-HA to cells or mice exposed to Br, Cl, or LMW-HA reversed these effects in vitro and improved AHR in vivo. We conclude that detrimental effects of halogen exposure on AHR are mediated via activation of the Ca-SR by LMW-HA.
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http://dx.doi.org/10.1152/ajplung.00429.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099432PMC
March 2020

TREK-1 and TRAAK Are Principal K Channels at the Nodes of Ranvier for Rapid Action Potential Conduction on Mammalian Myelinated Afferent Nerves.

Neuron 2019 12 17;104(5):960-971.e7. Epub 2019 Oct 17.

Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address:

Rapid conduction of nerve impulses is critical in life and relies on action potential (AP) leaps through the nodes of Ranvier (NRs) along myelinated nerves. While NRs are the only sites where APs can be regenerated during nerve conduction on myelinated nerves, ion channel mechanisms underlying the regeneration and conduction of APs at mammalian NRs remain incompletely understood. Here, we show that TREK-1 and TRAAK, the thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels, are clustered at NRs of rat trigeminal Aβ-afferent nerves with a density over 3,000-fold higher than that on their somas. These K2P channels, but not voltage-gated K channels as in other parts of nerves, are required for rapid AP repolarization at the NRs. Furthermore, these channels permit high-speed and high-frequency AP conduction along the myelinated afferent nerves, and loss of function of these channels at NRs retards nerve conduction and impairs sensory behavioral responses in animals.
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http://dx.doi.org/10.1016/j.neuron.2019.08.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895425PMC
December 2019

IL-1RA regulates immunopathogenesis during fungal-associated allergic airway inflammation.

JCI Insight 2019 11 1;4(21). Epub 2019 Nov 1.

Department of Microbiology and Immunology, Tulane University, New Orleans, Louisiana, USA.

Severe asthma with fungal sensitization (SAFS) defines a subset of human asthmatics with allergy to 1 or more fungal species and difficult-to-control asthma. We have previously reported that human asthmatics sensitized to fungi have worse lung function and a higher degree of atopy, which was associated with higher IL-1 receptor antagonist (IL-1RA) levels in bronchoalveolar lavage fluid. IL-1RA further demonstrated a significant negative association with bronchial hyperresponsiveness to methacholine. Here, we show that IL-1α and IL-1β are elevated in both bronchoalveolar lavage fluid and sputum from human asthmatics sensitized to fungi, implicating an association with IL-1α, IL-1β, or IL-1RA in fungal asthma severity. In an experimental model of fungal-associated allergic airway inflammation, we demonstrate that IL-1R1 signaling promotes type 1 (IFN-γ, CXCL9, CXCL10) and type 17 (IL-17A, IL-22) responses that were associated with neutrophilic inflammation and increased airway hyperreactivity. Each of these were exacerbated in the absence of IL-1RA. Administration of human recombinant IL-1RA (Kineret/anakinra) during fungal-associated allergic airway inflammation improved airway hyperreactivity and lowered type 1 and type 17 responses. Taken together, these data suggest that IL-1R1 signaling contributes to fungal asthma severity via immunopathogenic type 1 and type 17 responses and can be targeted for improving allergic asthma severity.
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http://dx.doi.org/10.1172/jci.insight.129055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948781PMC
November 2019

Sugarcoating Lung Injury: A Novel Role for High-Molecular-Weight Hyaluronan in Pneumonia.

Am J Respir Crit Care Med 2019 11;200(10):1197-1198

University of Alabama in BirminghamBirmingham, Alabama.

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http://dx.doi.org/10.1164/rccm.201908-1554EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857491PMC
November 2019

Phosgene inhalation causes hemolysis and acute lung injury.

Toxicol Lett 2019 Sep 30;312:204-213. Epub 2019 Apr 30.

Department of Anesthesiology and Perioperative Medicine, Birmingham, AL, 35205-3703, United States; Division of Molecular and Translational Biomedicine, Birmingham, AL, 35205-3703, United States; Pulmonary Injury and Repair Center, Birmingham, AL, 35205-3703, United States; Center for Free Radical Biology, Birmingham, AL, 35205-3703, United States; University of South Alabama Health College of Medicine, Mobile, AL, United States; St. Louis University, St. Louis, MO, 63104, United States. Electronic address:

Phosgene (Carbonyl Chloride, COCl) remains an important chemical intermediate in many industrial processes such as combustion of chlorinated hydrocarbons and synthesis of solvents (degreasers, cleaners). It is a sweet smelling gas, and therefore does not prompt escape by the victim upon exposure. Supplemental oxygen and ventilation are the only available management strategies. This study was aimed to delineate the pathogenesis and identify novel biomarkers of acute lung injury post exposure to COCl gas. Adult male and female C57BL/6 mice (20-25 g), exposed to COCl gas (10 or 20 ppm) for 10 min in environmental chambers, had a dose dependent reduction in PO and an increase in PCO, 1 day post exposure. However, mortality increased only in mice exposed to 20 ppm of COCl for 10 min. Correspondingly, these mice (20 ppm) also had severe acute lung injury as indicated by an increase in lung wet to dry weight ratio, extravasation of plasma proteins and neutrophils into the bronchoalveolar lavage fluid, and an increase in total lung resistance. The increase in acute lung injury parameters in COCl (20 ppm, 10 min) exposed mice correlated with simultaneous increase in oxidation of red blood cells (RBC) membrane, RBC fragility, and plasma levels of cell-free heme. In addition, these mice had decreased plasmalogen levels (plasmenylethanolamine) and elevated levels of their breakdown product, polyunsaturated lysophosphatidylethanolamine, in the circulation suggesting damage to cellular plasma membranes. This study highlights the importance of free heme in the pathogenesis of COCl lung injury and identifies plasma membrane breakdown product as potential biomarkers of COCl toxicity.
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http://dx.doi.org/10.1016/j.toxlet.2019.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653688PMC
September 2019

Role of fibroblast growth factor 23 and klotho cross talk in idiopathic pulmonary fibrosis.

Am J Physiol Lung Cell Mol Physiol 2019 07 1;317(1):L141-L154. Epub 2019 May 1.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, The University of Alabama , Birmingham, Alabama.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia that mainly affects the elderly. Several reports have demonstrated that aging is involved in the underlying pathogenic mechanisms of IPF. α-Klotho (KL) has been well characterized as an "age-suppressing" hormone and can provide protection against cellular senescence and oxidative stress. In this study, KL levels were assessed in human plasma and primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF-FB) and in lung tissue from mice exposed to bleomycin, which showed significant downregulation when compared with controls. Conversely, transgenic mice overexpressing KL were protected against bleomycin-induced lung fibrosis. Treatment of human lung fibroblasts with recombinant KL alone was not sufficient to inhibit transforming growth factor-β (TGF-β)-induced collagen deposition and inflammatory marker expression. Interestingly, fibroblast growth factor 23 (FGF23), a proinflammatory circulating protein for which KL is a coreceptor, was upregulated in IPF and bleomycin lungs. To our surprise, FGF23 and KL coadministration led to a significant reduction in fibrosis and inflammation in IPF-FB; FGF23 administration alone or in combination with KL stimulated KL upregulation. We conclude that in IPF downregulation of KL may contribute to fibrosis and inflammation and FGF23 may act as a compensatory antifibrotic and anti-inflammatory mediator via inhibition of TGF-β signaling. Upon restoration of KL levels, the combination of FGF23 and KL leads to resolution of inflammation and fibrosis. Altogether, these data provide novel insight into the FGF23/KL axis and its antifibrotic/anti-inflammatory properties, which opens new avenues for potential therapies in aging-related diseases like IPF.
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http://dx.doi.org/10.1152/ajplung.00246.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689746PMC
July 2019

Impaired Tumor-Necrosis-Factor-α-driven Dendritic Cell Activation Limits Lipopolysaccharide-Induced Protection from Allergic Inflammation in Infants.

Immunity 2019 01 8;50(1):225-240.e4. Epub 2019 Jan 8.

Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Infants have a higher risk of developing allergic asthma than adults. However, the underlying mechanism remains unknown. We show here that sensitization of mice with house-dust mites (HDMs) in the presence of low-dose lipopolysaccharide (LPS) prevented T helper 2 (Th2) cell allergic responses in adult, but not infant, mice. Mechanistically, adult CD11b migratory dendritic cells (mDCs) upregulated the transcription factor T-bet in response to tumor necrosis factor-α (TNF-α), which was rapidly induced after HDM + LPS sensitization. Consequently, adult CD11b mDCs produced interleukin-12 (IL-12), which prevented Th2 cell development by promoting T-bet upregulation in responding T cells. Conversely, infants failed to induce TNF-α after HDM + LPS sensitization. Therefore, CD11b mDCs failed to upregulate T-bet and did not secrete IL-12 and Th2 cell responses normally developed in infant mice. Thus, the availability of TNF-α dictates the ability of CD11b mDCs to suppress allergic Th2-cell responses upon dose-dependent endotoxin sensitization and is a key mediator governing susceptibility to allergic airway inflammation in infant mice.
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http://dx.doi.org/10.1016/j.immuni.2018.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335154PMC
January 2019

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

JCI Insight 2018 11 2;3(21). Epub 2018 Nov 2.

Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine.

Pulmonary fibrosis and emphysema are irreversible chronic events after inhalation injury. However, the mechanism(s) involved in their development remain poorly understood. Higher levels of plasma and lung heme have been recorded in acute lung injury associated with several insults. Here, we provide the molecular basis for heme-induced chronic lung injury. We found elevated plasma heme in chronic obstructive pulmonary disease (COPD) (GOLD stage 4) patients and also in a ferret model of COPD secondary to chronic cigarette smoke inhalation. Next, we developed a rodent model of chronic lung injury, where we exposed C57BL/6 mice to the halogen gas, bromine (Br2) (400 ppm, 30 minutes), and returned them to room air resulting in combined airway fibrosis and emphysematous phenotype, as indicated by high collagen deposition in the peribronchial spaces, increased lung hydroxyproline concentrations, and alveolar septal damage. These mice also had elevated pulmonary endoplasmic reticulum (ER) stress as seen in COPD patients; the pharmacological or genetic diminution of ER stress in mice attenuated Br2-induced lung changes. Finally, treating mice with the heme-scavenging protein, hemopexin, reduced plasma heme, ER stress, airway fibrosis, and emphysema. This is the first study to our knowledge to report elevated heme in COPD patients and establishes heme scavenging as a potential therapy after inhalation injury.
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http://dx.doi.org/10.1172/jci.insight.120694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238745PMC
November 2018

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

Am J Physiol Heart Circ Physiol 2019 01 31;316(1):H212-H223. Epub 2018 Oct 31.

Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.

Halogens are widely used, highly toxic chemicals that pose a potential threat to humans because of their abundance. Halogens such as bromine (Br) cause severe pulmonary and systemic injuries; however, the mechanisms of their toxicity are largely unknown. Here, we demonstrated that Br 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. Br-induced cardiac damage was demonstrated by acute (3-24 h) increases in circulating troponin I, heart-type fatty acid-binding protein, and NH-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 Br or Br reactant-exposed rats. Increased bromination of sarco(endo)plasmic reticulum Ca-ATPase (SERCA) and increased phosphalamban after Br inhalation decreased cardiac SERCA activity by 70%. SERCA inactivation was accompanied by increased Ca-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 (Br) 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 Br exposure but also defines calpains as a potential target to treat Br-induced toxicity.
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http://dx.doi.org/10.1152/ajpheart.00652.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383353PMC
January 2019

Influenza-mediated reduction of lung epithelial ion channel activity leads to dysregulated pulmonary fluid homeostasis.

JCI Insight 2018 10 18;3(20). Epub 2018 Oct 18.

Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine.

Severe influenza (IAV) infection can develop into bronchopneumonia and edema, leading to acquired respiratory distress syndrome (ARDS) and pathophysiology. Underlying causes for pulmonary edema and aberrant fluid regulation largely remain unknown, particularly regarding the role of viral-mediated mechanisms. Herein, we show that distinct IAV strains reduced the functions of the epithelial sodium channel (ENaC) and the cystic fibrosis transmembrane regulator (CFTR) in murine respiratory and alveolar epithelia in vivo, as assessed by measurements of nasal potential differences and single-cell electrophysiology. Reduced ion channel activity was distinctly limited to virally infected cells in vivo and not bystander uninfected lung epithelium. Multiple lines of evidence indicated ENaC and CFTR dysfunction during the acute infection period; however, only CFTR dysfunction persisted beyond the infection period. ENaC, CFTR, and Na,K-ATPase activities and protein levels were also reduced in virally infected human airway epithelial cells. Reduced ENaC and CFTR led to changes in airway surface liquid morphology of human tracheobronchial cultures and airways of IAV-infected mice. Pharmacologic correction of CFTR function ameliorated IAV-induced physiologic changes. These changes are consistent with mucous stasis and pulmonary edema; furthermore, they indicate that repurposing therapeutic interventions correcting CFTR dysfunction may be efficacious for treatment of IAV lung pathophysiology.
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http://dx.doi.org/10.1172/jci.insight.123467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237450PMC
October 2018

High molecular weight hyaluronan ameliorates allergic inflammation and airway hyperresponsiveness in the mouse.

Am J Physiol Lung Cell Mol Physiol 2018 11 6;315(5):L787-L798. Epub 2018 Sep 6.

Division of Intramural Research, National Institute of Environmental Health Sciences , Research Triangle Park, North Carolina.

Allergic asthma is a major cause of morbidity in both pediatric and adult patients. Recent research has highlighted the role of hyaluronan (HA), an extracellular matrix glycosaminoglycan, in asthma pathogenesis. Experimental allergic airway inflammation and clinical asthma are associated with an increase of shorter fragments of HA (sHA), which complex with inter-α-inhibitor heavy chains (HCs) and induce inflammation and airway hyperresponsiveness (AHR). Importantly, the effects of sHA can be antagonized by the physiological counterpart high molecular weight HA (HMWHA). We used a mouse model of house dust mite-induced allergic airway inflammation and demonstrated that instilled HMWHA ameliorated allergic airway inflammation and AHR, even when given after the establishment of allergic sensitization and after challenge exposures. Furthermore, instilled HMWHA reduced the development of HA-HC complexes and the activation of Rho-associated, coiled-coil containing protein kinase 2. We conclude that airway application of HMWHA is a potential treatment for allergic airway inflammation.
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http://dx.doi.org/10.1152/ajplung.00009.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425518PMC
November 2018

Resveratrol and ivacaftor are additive G551D CFTR-channel potentiators: therapeutic implications for cystic fibrosis sinus disease.

Int Forum Allergy Rhinol 2019 01 27;9(1):100-105. Epub 2018 Aug 27.

Department of Otolaryngology, University of Alabama at Birmingham, Birmingham, AL.

Background: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in defective Cl transport and cause chronic bacterial infections in the upper and lower airways of cystic fibrosis (CF) patients. Ivacaftor is a CFTR potentiator that improves Cl transport in CF patients with at least 1 copy of the G551D mutation. Resveratrol is also a potent CFTR potentiator that increases determinants of mucociliary transport. The objective of this study is to determine whether resveratrol and ivacaftor improve Cl secretion in G551D CFTR over either agent alone.

Methods: Fisher rat thyroid cells (FRT) transfected with G551D CFTR and human sinonasal epithelial cells (HSNE) containing the CFTR G551D mutation were subjected to pharmacologic manipulation of transepithelial ion transport in Ussing chambers. Activity was further evaluated using whole-cell patch clamp methods in G551D FRT cells.

Results: In G551D FRT cells, resveratrol (100 μM) and ivacaftor (10 μM) significantly increased Cl transport (change in short-circuit current, δI = μA/cm ) compared with single-agent and dimethylsulfoxide vehicle controls (resveratrol + ivacaftor 4.97 ± 0.57 vs ivacaftor 0.74 ± 0.12 vs resveratrol 2.96 ± 0.52 vs control 0.74 ± 0.12; p < 0.001). Maximal Cl secretion (20 μM forskolin) was also significantly enhanced (p < 0.0001). Activity was confirmed in G551D HSNE (resveratrol + ivacaftor 4.48 ± 0.39 vs ivacaftor 1.05 ± 0.11 vs. resveratrol 0.84 ± 0.3 vs control, 0.0 ± 0.02; p < 0.001), and whole-cell patch clamp analysis in G551D FRT cells (resveratrol + ivacaftor -2535 ± 179.3 pA vs ivacaftor -1408.9 ± 101.3 pA vs resveratrol; -766.2 ± 71.2 pA; p < 0.0001).

Conclusion: Additive improvement in G551D CFTR-mediated Cl secretion suggests that resveratrol could enhance ivacaftor therapy in these patients and improve CF-related rhinosinusitis.
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http://dx.doi.org/10.1002/alr.22202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318032PMC
January 2019

The common γ-chain cytokine IL-7 promotes immunopathogenesis during fungal asthma.

Mucosal Immunol 2018 09 15;11(5):1352-1362. Epub 2018 Jun 15.

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Asthmatics sensitized to fungi are reported to have more severe asthma, yet the immunopathogenic pathways contributing to this severity have not been identified. In a pilot assessment of human asthmatics, those subjects sensitized to fungi demonstrated elevated levels of the common γ-chain cytokine IL-7 in lung lavage fluid, which negatively correlated with the lung function measurement PC20. Subsequently, we show that IL-7 administration during experimental fungal asthma worsened lung function and increased the levels of type 2 cytokines (IL-4, IL-5, IL-13), proallergic chemokines (CCL17, CCL22) and proinflammatory cytokines (IL-1α, IL-1β). Intriguingly, IL-7 administration also increased IL-22, which we have previously reported to drive immunopathogenic responses in experimental fungal asthma. Employing IL22R26R reporter mice, we identified γδ T cells, iNKT cells, CD4 T cells and ILC3s as sources of IL-22 during fungal asthma; however, only iNKT cells were significantly increased after IL-7 administration. IL-7-induced immunopathogenesis required both type 2 and IL-22 responses. Blockade of IL-7Rα in vivo resulted in attenuated IL-22 production, lower CCL22 levels, decreased iNKT cell, CD4 T-cell and eosinophil recruitment, yet paradoxically increased dynamic lung resistance. Collectively, these results suggest a complex role for IL-7 signaling in allergic fungal asthma.
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http://dx.doi.org/10.1038/s41385-018-0028-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319622PMC
September 2018

Halogen Inhalation-Induced Lung Injury and Acute Respiratory Distress Syndrome.

Chin Med J (Engl) 2018 May;131(10):1214-1219

Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Objective: Exposure to halogens, such as chlorine or bromine, results in environmental and occupational hazard to the lung and other organs. Chlorine is highly toxic by inhalation, leading to dyspnea, hypoxemia, airway obstruction, pneumonitis, pulmonary edema, and acute respiratory distress syndrome (ARDS). Although bromine is less reactive and oxidative than chlorine, inhalation also results in bronchospasm, airway hyperresponsiveness, ARDS, and even death. Both halogens have been shown to damage the systemic circulation and result in cardiac injury as well. There is no specific antidote for these injuries since the mechanisms are largely unknown.

Data Sources: This review was based on articles published in PubMed databases up to January, 2018, with the following keywords: "chlorine," "bromine," "lung injury," and "ARDS."

Study Selection: The original articles and reviews including the topics were the primary references.

Results: Based on animal studies, it is found that inhaled chlorine will form chlorine-derived oxidative products that mediate postexposure toxicity; thus, potential treatments will target the oxidative stress and inflammation induced by chlorine. Antioxidants, cAMP-elevating agents, anti-inflammatory agents, nitric oxide-modulating agents, and high-molecular-weight hyaluronan have shown promising effects in treating acute chlorine injury. Elevated free heme level is involved in acute lung injury caused by bromine inhalation. Hemopexin, a heme-scavenging protein, when administered postexposure, decreases lung injury and improves survival.

Conclusions: At present, there is an urgent need for additional research to develop specific therapies that target the basic mechanisms by which halogens damage the lungs and systemic organs.
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http://dx.doi.org/10.4103/0366-6999.231515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956773PMC
May 2018

Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and Chronic Aspergillus fumigatus Exposure.

Infect Immun 2018 07 21;86(7). Epub 2018 Jun 21.

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

Chitin is a polysaccharide that provides structure and rigidity to the cell walls of fungi and insects. Mammals possess multiple chitinases, which function to degrade chitin, thereby supporting a role for chitinases in immune defense. However, chitin degradation has been implicated in the pathogenesis of asthma. Here, we determined the impact of acidic mammalian chitinase (AMCase) () deficiency on host defense during acute exposure to the fungal pathogen as well as its contribution to -associated allergic asthma. We demonstrate that chitin in the fungal cell wall was detected at low levels in conidia, which emerged at the highest level during hyphal transition. In response to acute challenge, mice unexpectedly demonstrated lower lung burdens at 2 days postchallenge. The lower fungal burden correlated with decreased lung interleukin-33 (IL-33) levels yet increased IL-1β and prostaglandin E (PGE) production, a phenotype that we reported previously to promote the induction of IL-17A and IL-22. During chronic exposure, AMCase deficiency resulted in lower dynamic and airway lung resistance than in wild-type mice. Improved lung physiology correlated with attenuated levels of the proallergic chemokines CCL17 and CCL22. Surprisingly, examination of inflammatory responses during chronic exposure revealed attenuated IL-17A and IL-22 responses, but not type 2 responses, in the absence of AMCase. Collectively, these data suggest that AMCase functions as a negative regulator of immune responses during acute fungal exposure and is a contributor to fungal asthma severity, putatively via the induction of proinflammatory responses.
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http://dx.doi.org/10.1128/IAI.00944-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013657PMC
July 2018