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Cellular responses following ex vivo lung exposure to the nerve agent VX - Potential for additional treatment
Elisabeth Wigenstam1, Anders Bucht1, Lina Thors1
1Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
Abstract:
Following inhalation exposure to organophosphorus nerve agents, symptoms rapidly develop and severe respiratory symptoms, such as bronchorrhea and bronchoconstriction are the leading causes of lethality. Nerve agent-induced lung injury is little investigated and the standard treatment for symptomatic relief targets the enzyme acetylcholinesterase and muscarinic acetylcholine and GABAergic receptors. In the present study, cellular responses in lung tissue during the acute (40 min) and extended phase (24 h) following severe exposure to the nerve agent VX have been investigated using an ex vivo rat precision-cut lung slice model including electrostimulation to induce a cholinergic response. Changes in protein amount, cell viability, together with, inflammatory and oxidative stress markers have been determined in both the lung tissue and incubation medium. During the acute phase, VX caused significantly increased airway contraction and decreased airway relaxation. Five micromolar of VX did not affect the sample protein levels and cell viability in lung tissue. Among seven markers of cellular responses investigated in the lung tissue, increased levels of heme oxygenase-1 and matrix metalloproteinase-9 together with decreased levels of glutathione in the incubation medium were observed in the acute phase following VX-exposure compared to electrostimulation only. No difference in cellular response was observed following VX-exposure for 24 h compared to the air control. In comparison, LPS-exposure resulted in time-dependent changes in all markers of inflammation and oxidative response. In conclusion, the present study demonstrated VX-specific patterns of oxidative responses in the lung, as well as, signs of inflammatory response and remodelling of extracellular matrix. These potential mechanisms of tissue injury should be further investigated for their potential as additional therapeutic targets during the acute phase of intoxication.
Insights
Organophosphorus nerve agent VX causes acute lung injury with airway constriction and oxidative stress. These VX-specific lung responses may offer new therapeutic targets during intoxication.
Area of Science:
- Toxicology
- Pulmonary Medicine
- Pharmacology
Background:
- Organophosphorus nerve agents cause rapid, lethal respiratory symptoms.
- Lung injury from nerve agents is understudied.
- Current treatments focus on symptomatic relief via enzyme and receptor targets.
Purpose of the Study:
- Investigate cellular responses in rat lung tissue after VX nerve agent exposure.
- Examine acute (40 min) and extended (24 h) phases post-exposure.
- Identify potential therapeutic targets for VX-induced lung injury.
Main Methods:
- Used an ex vivo rat precision-cut lung slice model.
- Electrostimulation induced a cholinergic response.
- Assessed protein levels, cell viability, and inflammatory/oxidative stress markers.
Main Results:
- VX exposure caused acute airway contraction and reduced relaxation.
- Increased heme oxygenase-1 and matrix metalloproteinase-9 observed.
- Decreased glutathione levels in incubation medium noted in the acute phase.
- No significant cellular response differences at 24 h post-VX exposure compared to controls.
- LPS exposure showed time-dependent inflammatory and oxidative changes.
Conclusions:
- VX exposure induces specific oxidative responses in the lung.
- Signs of inflammation and extracellular matrix remodeling were observed.
- These mechanisms represent potential therapeutic targets during acute VX intoxication.
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