Airway epithelial damage induced by sulfur mustard in uinea pigs, effects of glucocorticoids

1996 ◽  
Vol 15 (12) ◽  
pp. 964-971 ◽  
Author(s):  
JH Calvet ◽  
A. Coste ◽  
M. Levame ◽  
A. Harf ◽  
I. Macquin-Mavier ◽  
...  
Keyword(s):  
Cell Density ◽  
Guinea Pigs ◽  
Sulfur Mustard ◽  
Chemical Warfare Agent ◽  
Tracheal Epithelium ◽  
Basal Cells ◽  
Airway Epithelial ◽  
Epithelial Damage ◽  
Epithelium Regeneration ◽  
Cell Shedding

Sulfur mustard (SM) represents a potential chemical warfare agent. In order to characterize SM-induced airway epithelial damage, we studied the effects of an intratracheal injection of 0.3 mg/kg of SM in guinea pigs, 5 h, 24 h, 14 days and 35 days after exposure. During the acute period, lesions prevailed in tracheal epithelium exhibiting intra-epithelial blisters, inflammatory cell infiltration and columnar cell shedding with exposure of basal cells. Fourteen days after intoxication, tracheal epithelium appeared disorganized and showed a signifi cant decrease in height and cell density. Tracheal epithelium recovery was still not complete even 35 days after SM-intoxication. At day 14, in SM-intoxicated guinea pigs treated with betamethasone from day 7 to day 14, epithelium height, cell density and cell proliferation (evaluated by immunohistochemistry) were significantly increased compared to untreated guinea pigs. In conclu sion, the lesions observed in SM-intoxicated guinea pigs seem to be in accordance with clinical human observa tions and are relevant to the study of airway epithelial damage induced by SM. This animal model could be used to illustrate tracheal epithelium regeneration mainly derived from basal cells and to show glucocorticoid effects on airway epithelial recovery after chemical aggression.

Acute and chronic respiratory effects of sulfur mustard intoxication in guinea pig

1994 ◽  
Vol 76 (2) ◽  
pp. 681-688 ◽  
Author(s):  
J. H. Calvet ◽  
P. H. Jarreau ◽  
M. Levame ◽  
M. P. D′Ortho ◽  
H. Lorino ◽  
...  
Keyword(s):  
Substance P ◽  
Guinea Pigs ◽  
Sulfur Mustard ◽  
Neutral Endopeptidase ◽  
Chemical Warfare Agent ◽  
Airway Hyperreactivity ◽  
Tracheal Epithelium ◽  
Endopeptidase Activity ◽  
Respiratory System Resistance ◽  
Cell Shedding

Sulfur mustard (SM) has been used as a vesicant chemical warfare agent. To investigate the respiratory damages it causes, we studied the effects on guinea pigs of an intratracheal injection of 0.3 mg/kg of SM 5 h and 14 days after injection. Five hours after SM intoxication, respiratory system resistance and microvascular permeability were increased. These alterations were not prevented by pretreatment with 50 mg/kg sc of capsaicin 2 wk before SM intoxication. Histological studies showed columnar cell shedding all along the tracheal epithelium, bronchoconstriction, and peribronchial edema. Fourteen days after SM intoxication, guinea pigs demonstrated airway hyperreactivity to aerosolized substance P and histamine. Pretreatment with phosphoramidon caused a further increase in airway responsiveness to substance P. Neutral endopeptidase activity in the tracheal epithelium was decreased by twofold in SM-intoxicated guinea pigs. At this stage, the tracheal epithelium was disorganized and atrophic. These results demonstrate that in guinea pigs SM intoxication induces severe lesions to the tracheal epithelium, which might account for the airway hyperresponsiveness observed 14 days after intoxication.

Effect of doxycycline on sulfur mustard-induced respiratory lesions in guinea pigs

2005 ◽  
Vol 289 (1) ◽  
pp. L67-L74 ◽  
Author(s):  
Christophe Guignabert ◽  
Laurent Taysse ◽  
Jean-Henri Calvet ◽  
Emmanuelle Planus ◽  
Séraphin Delamanche ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Inflammatory Cell ◽  
Sulfur Mustard ◽  
Chemical Warfare Agent ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Therapeutic Tool ◽  
Gelatinase Activity ◽  
In Situ Zymography ◽  
Epithelial Lesions

Respiratory tract lesions induced by the chemical warfare agent sulfur mustard (SM) are characterized by epithelial damages associated with inflammatory cell infiltration. Here we evaluated the imbalance between gelatinase and tissue inhibitors of metalloproteinases (TIMPs), and we tested pretreatment with the protease inhibitor doxycycline. Guinea pigs were intoxicated intratracheally with SM and evaluated 24 h after exposure. Matrix metalloproteinase (MMP) gelatinase activity of bronchial lavage (BL) fluid from SM-exposed guinea pigs was high compared with controls, as shown by both zymography and biotinylated substrate degradation, whereas TIMP-1 and -2 levels by immunoblotting were similar. Extensive areas of lysis were evidenced by in situ zymography, indicating imbalance between gelatinases and inhibitors towards net proteolytic activity. Doxycycline pretreatment resulted in 1) decreased gelatinase activity (zymography, free gelatinase activity assay, and in situ zymography); 2) decreased inflammation (BL fluid cellularity and protein level); and 3) dramatic decrease in histological epithelial lesions. Our results suggest inadequate levels of TIMP to counteract increased gelatinase activity and further support a role for MMP gelatinases in SM-induced respiratory lesions. They also suggest that doxycycline may hold promise as a therapeutic tool.

Mustard-gas skin lesion and bullous pemphigoid antigen

1994 ◽  
Vol 52 ◽  
pp. 254-255
Author(s):  
John P. Petrali ◽  
Susan B. Oglesby ◽  
Tracey A. Hamilton
Keyword(s):  
Bullous Pemphigoid ◽  
Sulfur Mustard ◽  
Repair Process ◽  
Chemical Warfare Agent ◽  
Mustard Gas ◽  
Basal Cells ◽  
Immunochemical Study ◽  
Bullous Pemphigoid Antigen ◽  
Type Iv ◽  
Bullous Diseases

Human dermal exposure to the chemical warfare agent, sulfur mustard gas (HD), results in the delayed formation of fluid filled bullae which are incapacitating, persistent and slow to heal. In animal investigations, the pathology is typically described as that occurring during a prevesication period and that of a vesication period. During the first 24 hours, the pathology involves the latent lethal targeting of epidermal basal cells, a disabling of hemidesmosomes (prevesication) and a progressive inflammatory edema of the lamina lucida all contributing to the formation of characteristic lucidolytic microvesicles persisting at the dermal epidermal junction (vesication). We are now investigating possible primary or secondary HD-induced effects on extracellular adherent structural proteins of the basement membrane microenvironment which may contribute to vesication or may influence the repair process. Proteins selected for immunochemical study were laminin, type IV collagen, bullous pemphigoid antigen (BPA), fibronectin and desmosomal protein.Effects on BPA were of special interest. Its epitopes, BPA1 and BPA2, have been anatomically localized to basal cell hemidesmosomes and lamina lucida, and its role as an autoimmune antigen in the etiology of clinical bullous diseases such as bullous pemphigoid is well documented.

Changes in permeability of dog tracheal epithelium in response to hydrostatic pressure

1992 ◽  
Vol 262 (2) ◽  
pp. L176-L182 ◽  
Author(s):  
M. Kondo ◽  
W. E. Finkbeiner ◽  
J. H. Widdicombe
Keyword(s):  
Hydrostatic Pressure ◽  
Fluorescein Isothiocyanate ◽  
Tracheal Epithelium ◽  
Maximal Effect ◽  
Airway Epithelial ◽  
Blood Proteins ◽  
Epithelial Damage ◽  
Ussing Chambers ◽  
Submucosal Edema ◽  
Tissue Ultrastructure

We tested the hypothesis that, in asthma, the airway epithelial damage and leakage of blood proteins into the lumen are the result of edema and raised submucosal hydrostatic pressure. Sheets of dog tracheal epithelium were mounted in Ussing chambers, and the effects of transepithelial hydrostatic pressure differences (delta P) on conductance (G), [3H]mannitol flux (Jman), and fluorescein isothiocyanate-albumin flux (Jalb) were determined. delta P values of 20 cmH2O directed from the mucosal to submucosal side of the tissue (m----s) had no significant effects on G, Jman, Jalb, or tissue ultrastructure. delta Ps----;m caused increases in conductance (G) with a maximal effect at approximately 20 cmH2O. delta Ps----m of 20 cmH2O significantly (P less than 0.05) increased G (4.3 +/- 0.6 to 10.6 +/- 1.6 mS/cm2), Jman s—m (18 +/- 5 to 411 +/- 54 nmol.cm-2.h-1), J(alb)s----m (0.3 +/- 0.1 to 6.0 +/- 2.0 micrograms.cm-2.h-1), and J(alb)m—s (0.7 +/- 0.3 to 1.8 +/- 0.4 micrograms.cm-2.h-1). Jman m----s was not affected. On removal of delta P, G and Jman s----m returned to preexposure values, though J(alb)s----m remained slightly elevated at 1.1 +/- 0.3 micrograms.cm-2.h-1. Morphologically, delta Ps----m caused dilation of lateral intercellular spaces, disruption of tight junctions, and submucosal edema. The large increases in s----m fluxes of albumin and mannitol are consistent with bulk flow of fluid toward the lumen via the areas of epithelial damage.

Glucocorticoids inhibit sulfur mustard-induced airway muscle hyperresponsiveness to substance P

1994 ◽  
Vol 77 (5) ◽  
pp. 2325-2332 ◽  
Author(s):  
J. H. Calvet ◽  
M. P. D'Ortho ◽  
P. H. Jarreau ◽  
M. Levame ◽  
A. Harf ◽  
...  
Keyword(s):  
Substance P ◽  
Guinea Pigs ◽  
Contractile Response ◽  
Sulfur Mustard ◽  
Neutral Endopeptidase ◽  
Airway Hyperreactivity ◽  
Tracheal Epithelium ◽  
Solvent Treatment ◽  
Tracheal Epithelial ◽  
Intratracheal Injection

To explore the mechanisms of airway hyperreactivity to aerosolized substance P observed in guinea pigs 14 days after intratracheal injection of sulfur mustard (SM), we studied the effects of epithelium removal and inhibition of neutral endopeptidase (NEP) activity on airway muscle responsiveness. Tracheal rings from SM-intoxicated guinea pigs expressed a greater contractile response to substance P than rings from nonintoxicated guinea pigs. After epithelium removal or incubation with the NEP inhibitor phosphoramidon, the contractile responses of tracheal rings to substance P did not differ in guinea pigs injected with SM or ethanol (SM solvent). Treatment of the guinea pigs with betamethasone for 7 days before measurement abolished the airway muscle hyperresponsiveness observed in untreated SM-intoxicated guinea pigs and partially restored tracheal epithelium NEP activity. In addition, the tracheal epithelium height and cell density of SM-intoxicated guinea pigs treated with betamethasone were significantly greater than in those without betamethasone. These results demonstrate that SM intoxication induces airway muscle hyperresponsiveness to substance P by reducing tracheal epithelial NEP activity and that glucocorticoids might inhibit this hyperresponsiveness by increasing this activity.

Blocking Cell Extrusion Prevents Bronchoconstriction-Induced Airway Epithelial Damage and Inflammation

2019 ◽  
Author(s):  
Dustin Bagley ◽  
Kristina Fox ◽  
Paulina Frances Redd ◽  
Merry Joseph ◽  
Elena Ortiz-Zapater ◽  
...  
Keyword(s):  
Airway Epithelial ◽  
Epithelial Damage ◽  
Cell Extrusion

scholarly journals PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aubrey N. Michi ◽  
Bryan G. Yipp ◽  
Antoine Dufour ◽  
Fernando Lopes ◽  
David Proud
Keyword(s):  
Host Defense ◽  
Barrier Function ◽  
Bacterial Infections ◽  
Molecular Mechanisms ◽  
Cellular Damage ◽  
Epithelial Barrier ◽  
Airway Epithelial ◽  
Barrier Dysfunction ◽  
Epithelial Barrier Function ◽  
Epithelial Damage

AbstractHuman rhinoviruses (HRV) are common cold viruses associated with exacerbations of lower airways diseases. Although viral induced epithelial damage mediates inflammation, the molecular mechanisms responsible for airway epithelial damage and dysfunction remain undefined. Using experimental HRV infection studies in highly differentiated human bronchial epithelial cells grown at air-liquid interface (ALI), we examine the links between viral host defense, cellular metabolism, and epithelial barrier function. We observe that early HRV-C15 infection induces a transitory barrier-protective metabolic state characterized by glycolysis that ultimately becomes exhausted as the infection progresses and leads to cellular damage. Pharmacological promotion of glycolysis induces ROS-dependent upregulation of the mitochondrial metabolic regulator, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), thereby restoring epithelial barrier function, improving viral defense, and attenuating disease pathology. Therefore, PGC-1α regulates a metabolic pathway essential to host defense that can be therapeutically targeted to rescue airway epithelial barrier dysfunction and potentially prevent severe respiratory complications or secondary bacterial infections.

scholarly journals Alkylated epidermal creatine kinase as a biomarker for sulfur mustard exposure: comparison to adducts of albumin and DNA in an in vivo rat study

2021 ◽  
Author(s):  
Dirk Steinritz ◽  
Robin Lüling ◽  
Markus Siegert ◽  
Julia Herbert ◽  
Harald Mückter ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Dna Adducts ◽  
Sulfur Mustard ◽  
Ex Vivo ◽  
Immunomagnetic Separation ◽  
Chemical Warfare Agent ◽  
Cysteine Residue ◽  
Islamic State ◽  
Rat Skin

AbstractSulfur mustard (SM) is a chemical warfare agent which use is banned under international law and that has been used recently in Northern Iraq and Syria by the so-called Islamic State. SM induces the alkylation of endogenous proteins like albumin and hemoglobin thus forming covalent adducts that are targeted by bioanalytical methods for the verification of systemic poisoning. We herein report a novel biomarker, namely creatine kinase (CK) B-type, suitable as a local biomarker for SM exposure on the skin. Human and rat skin were proven to contain CK B-type by Western blot analysis. Following exposure to SM ex vivo, the CK-adduct was extracted from homogenates by immunomagnetic separation and proteolyzed afterwards. The cysteine residue Cys282 was found to be alkylated by the SM-specific hydroxyethylthioethyl (HETE)-moiety detected as the biomarker tetrapeptide TC(-HETE)PS. A selective and sensitive micro liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry (µLC-ESI MS/HRMS) method was developed to monitor local CK-adducts in an in vivo study with rats percutaneously exposed to SM. CK-adduct formation was compared to already established DNA- and systemic albumin biomarkers. CK- and DNA-adducts were successfully detected in biopsies of exposed rat skin as well as albumin-adducts in plasma. Relative biomarker concentrations make the CK-adduct highly appropriate as a local dermal biomarker. In summary, CK or rather Cys282 in CK B-type was identified as a new, additional dermal target of local SM exposures. To our knowledge, it is also the first time that HETE-albumin adducts, and HETE-DNA adducts were monitored simultaneously in an in vivo animal study.

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