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Published on: May 4, 2021
Effects of inducible nitric oxide synthase inhibitors on asthma depending on administration schedule
Masayoshi Abe1, Yuri Hayashi, Akira Murai
1Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan. abemasa@fukuoka-u.ac.jp
Abstract:
The effectiveness of two inducible nitric oxide synthase (iNOS) inhibitors on allergic airway inflammation was investigated under different administration schedules. Rats sensitized to ovalbumin (OVA) were exposed to OVA for 3 consecutive days. Both iNOS inhibitors showed markedly different effects between two pretreatment schedules: pretreatment before each of three OVA exposures S1 and before the third exposure alone S2. S1 pretreatment resulted in higher pulmonary resistance than triple OVA alone. This potentiation was associated with increased eosinophil infiltration and malondialdehyde levels in the lungs, which were suppressed by superoxide dismutases (SODs) but not by methylprednisolone. However, the S2 administration of both iNOS inhibitors completely suppressed the airway response. Administration by schedule S1 completely suppressed plasma nitrite and nitrate levels, but that by S2 caused only a slight suppression. The triple OVA exposures resulted in the upregulation of iNOS in alveolar macrophages and arginase activity, Mn- and Cu/Zn-SOD expression, and nitrotyrosine and lipid peroxide deposition in the airway. However, inhibitors administered by schedule S1 suppressed this upregulation, but further potentiated nitrotyrosine, which in turn was inhibited by SOD. Although iNOS inhibitors may be beneficial for asthma, repeated administration may be detrimental because of extensive reduction of NO and downregulation of SOD.
Insights
Investigating inducible nitric oxide synthase (iNOS) inhibitors for allergic airway inflammation revealed that repeated administration may be detrimental. However, a single dose effectively suppressed airway responses, suggesting potential therapeutic benefits in asthma treatment.
Area of Science:
- Allergy and immunology
- Pharmacology
- Respiratory medicine
Background:
- Allergic airway inflammation is a complex condition involving multiple cellular and molecular pathways.
- Inducible nitric oxide synthase (iNOS) plays a role in airway inflammation, but its precise contribution and the effects of its inhibition are not fully understood.
Purpose of the Study:
- To investigate the effectiveness of two iNOS inhibitors on allergic airway inflammation in a rat model.
- To compare the effects of different administration schedules (S1: pretreatment before each exposure; S2: pretreatment before the final exposure) on therapeutic outcomes.
Main Methods:
- Rats sensitized to ovalbumin (OVA) were exposed to OVA and treated with iNOS inhibitors under two different schedules.
- Pulmonary resistance, inflammatory cell infiltration, biochemical markers (malondialdehyde, nitrite/nitrate), and enzyme/protein expression (iNOS, arginase, SODs, nitrotyrosine) were assessed.
Main Results:
- Schedule S1 (repeated pretreatment) potentiated airway inflammation, increasing pulmonary resistance and eosinophil infiltration, while S2 (single pretreatment) completely suppressed the airway response.
- S1 administration suppressed plasma nitrite/nitrate levels, whereas S2 caused only slight suppression. S1 also upregulated nitrotyrosine, which was mitigated by superoxide dismutases (SODs).
- OVA exposure upregulated iNOS, arginase, SODs, and nitrotyrosine in the airway; S1 inhibitors suppressed iNOS upregulation but potentiated nitrotyrosine.
Conclusions:
- While iNOS inhibitors show promise for asthma treatment, repeated administration may be detrimental due to excessive nitric oxide (NO) reduction and SOD downregulation.
- A single administration schedule (S2) effectively suppressed airway inflammation, suggesting a potential therapeutic window for iNOS inhibition in allergic airway diseases.
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