Sulfonamides are Protective in Lung Ischemia-Reperfusion Injury by Carbonic Anhydrase Inhibition and Other Mechanisms
Akshay Kumar1, Erik Swenson2.
1University of Pittsburgh, Pittsburgh, PA, USA, 2VA Puget Sound Health Care System, University of Washington, Seattle, WA, USA.
OBJECTIVE : Protective action of carbonic anhydrase (CA) inhibition against ischemia-reperfusion (I/R) injury in the heart has been demonstrated but effect on lungs are unknown. We studied effects of acetazolamide (AZ), benzolamide (BZ), and a non-CA inhibiting analog of acetazolamide (n-methyl acetazolamide-NMA) in acute lung I/R injury.
METHODS: 30 healthy male rats (300-350 g, 6-8 weeks old) were randomly classified into six groups: Sham, I/R injury treated with saline, I/R injury + 30 mg/kg BZ pretreatment, I/R injury + 30 mg/kg AZ pretreatment and I/R injury + 30 mg/kg NMA pretreatment. For the IR injury, the left main pulmonary artery and bronchus were clamped for 60 minutes and then blood flow was reestablished for 90 minutes, after which measurements were taken and tissue samples obtained.
RESULTS: AZ, NMA, but not BZ, significantly reduced the fall in PaO2/FIO2, caused by lung I/R injury. The rise in lung dry/wet weight and protein extravasation (reflecting capillary permeability) were reduced by all pretreatments. The lungs in pretreatment groups showed less neutrophilic infiltration, alveolar edema and hemorrhage. Lastly, drug pretreatments all reduced HIF-1 activation, suggestive of less tissue hypoxia with I/R injury.
CONCLUSIONS : Our data demonstrate that pretreatment with AZ, BZ and NMA all protect against and mitigate the extent of damage with I/R in the lung. This appears to involve direct effects of CA inhibition; in the case of NMA, actions independent of CA inhibition like anti-oxidative or hypoxia-mediated Ca++ signaling changes, as has been shown in the uninjured hypoxic pulmonary vasculature.
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