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| Year : 2003 | Volume
: 49
| Issue : 1 | Page : 17-20 |
Prevention of reperfusion lung injury by lidocaine in isolated rat lung ventilated with higher oxygen levels.
KC Das, HP Misra
University of Texas Health Center at Tyler, 11937 US Hwy 271, Tyler, TX 75708, USA. , USA
Correspondence Address:
K C Das
University of Texas Health Center at Tyler, 11937 US Hwy 271, Tyler, TX 75708, USA.
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0022-3859.934
BACKGROUND: Lidocaine, an antiarrhythmic drug has been shown to be effective against post-ischaemic reperfusion injury in heart. However, its effect on pulmonary reperfusion injury has not been investigated. AIMS: We investigated the effects of lidocaine on a postischaemic reperfused rat lung model. MATERIALS AND METHODS: Lungs were isolated and perfused at constant flow with Krebs-Henseilet buffer containing 4% bovine serum albumin, and ventilated with 95% oxygen mixed with 5% CO2. Lungs were subjected to ischaemia by stopping perfusion for 60 minutes followed by reperfusion for 10 minutes. Ischaemia was induced in normothermic conditions. RESULTS: Postischaemic reperfusion caused significant (p < 0.0001) higher wet-to-dry lung weight ratio, pulmonary arterial pressure and peak airway pressure compared to control lungs. Lidocaine, at a dose of 5mg/Kg b.w. was found to significantly (p < 0.0001) attenuate the increase in the wet-to-dry lung weight ratio, pulmonary arterial pressure and peak airway pressure observed in post-ischaemic lungs. CONCLUSION: Lidocaine is effective in preventing post-ischaemic reperfusion injury in isolated, perfused rat lung.
Keywords: Animal, Comparative Study, Lidocaine, pharmacology,Lung, drug effects,Male, Models, Animal, Oxygen, administration &dosage,Rats, Rats, Sprague-Dawley, Reperfusion Injury, prevention &control,Support, U.S. Gov′t, P.H.S.,
How to cite this article:
Das K C, Misra H P. Prevention of reperfusion lung injury by lidocaine in isolated rat lung ventilated with higher oxygen levels. J Postgrad Med 2003;49:17-20 |
How to cite this URL:
Das K C, Misra H P. Prevention of reperfusion lung injury by lidocaine in isolated rat lung ventilated with higher oxygen levels. J Postgrad Med [serial online] 2003 [cited 2023 Jun 10];49:17-20. Available from: https://www.jpgmonline.com/text.asp?2003/49/1/17/934 |
Ventilation with high levels of O2 has been shown to be associated with acute lung injury.[1],[2],[3] Lungs exposed to higher O2 tension in the absence of circulation was found to produce large amounts of free radicals.[4] Koyama et al. have demonstrated the involvement of oxygen-derived radicals in acute lung injury when canine lung lobes were ventilated with 95% O2.[5] In another recent study, Fisher et al. have shown increased production of lipid peroxides when 95% O2 was administered during ischaemic ventilation in isolated rat lung.[6] Lipid peroxidation mediated by hydroxyl radicals has been suggested as a possible mechanism of pulmonary injury.[7],[8],[9] Additionally, activated forms of oxygen also increase pulmonary arterial pressure, and increase vascular permeability resulting in the formation of a protein-rich intra-alveolar oedema.[10],[11],[12] If these toxic forms of oxygen are not properly neutralized by endogenous antioxidants, they can interact with cell membrane to generate lipid peroxides, lipid hydroperoxides, lipid endoperoxides and arachidonic acid metabolites.[11] Lidocaine is a widely used drug with significant stabilizing activity on lipid biomembranes.[12] In addition, lidocaine was found to reduce thiourea-induced pulmonary vascular protein leak in rats.[12] Furthermore, lidocaine was reported to reduce canine infarct size, and was shown to decrease the release of conjugated diene, a marker of lipid peroxidation.[13] We have earlier reported that lidocaine is a potent hydroxyl radical scavenger and quencher of singlet oxygen.[14] We have also demonstrated that lidocaine can inhibit NADPH-dependent lipid peroxidation in bovine lung microsomes.[15] Since lipid peroxidation can be initiated by reactive forms of oxygen,[7],[8],[9] and lipid peroxide products accumulate in O2 ventilated ischaemic lungs, we hypothesised that lidocaine can prevent post-ischaemic reperfusion injury in O2 ventilated lungs. We present evidence in this report that lidocaine prevents ischaemia-reperfusion lung injury in isolated O2 ventilated perfused rat lung.
Male Sprague-Dawley rats (Harlan’s Sprague-Dawley) weighing 300-500 gms, were anesthetised with 64.8 mg/Kg ip pentobarbital sodium (Anthony products Co., Arcadia, CA). A tracheostomy was performed that permitted ventilation with a Harvard rodent ventilator (model 683) at 62 strokes per min, a tidal volume of 2.3 to 3 ml, and positive end expiratory pressure of 2.5 cm H2O. The inspired gas mixture was 95% oxygen with 5% CO2 (Analyzed, Industrial gas Co. Denver). Subsequently a median sternotomy was performed, heparin (200 IU) was injected into the right ventricle, and cannulas were placed in the pulmonary artery and left ventricle. The heart, lungs and mediastinal structures were removed en bloc and suspended from a Fort-250 (World Precision Instruments (WPI), New Haven, Connecticut) rigid linear force transducer to monitor any weight change and placed in the humidified chamber. The lungs were perfused by a masterflex (Cole Parmer Instruments, Vernon Hills, IL) pump with Krebs-Henseilet buffer at a constant flow of 0.05ml/min/gm of b.w. The Krebs-Hanseilet buffer contained (in mM) 118 NaCl, 4.7 KCl, 1.17 MgSO4, 25 NaHCO3, 1.18 KH2PO4, 1.90 CaCl2, 11.1 glucose and 4% bovine serum albumin (66000 MW, Sigma Chemical Co, St Louis, MO). The pH of the perfusate was maintained between 7.35-7.45 by periodic addition of sodium bicarbonate and constant monitoring. All chemicals were purchased from Sigma Chemical Co. (St Louis, MO).
The first 50 ml of lung effluent was discarded to eliminate circulating rat blood elements from the vascular space of the lung. Subsequently a recirculating mode was established with 50 ml of perfusate. Pulmonary artery pressure (Pa) was constantly monitored with a blood pressure transducer BPLR-0111 (WPI). Peak air way pressure was constantly monitored by a PNEU-01 (WPI) pressure transducer. The pressure transducers were calibrated with a blood pressure measurement instrument (The Lumiscope, Co. Japan). Mean Pa pressure, change in lung weight and mean peak air way pressure were constantly monitored through the pressure transducer and linear force transducers, respectively, connected to an amplifier bridge (WPI). The bridge was connected to a MacLab-4 (WPI) which was in turn connected to a Macintosh SE computer. The data were recorded by Scope V3.1 software for the Maclab system (WPI).
After initiation of the closed recirculating system, isolated lungs were observed for 10 minutes to ensure a stable preparation. After a total 10 minutes of perfusion, the lungs were subjected to ischaemic injury for 60 min by stopping perfusion. Ventilation was continued with 95% oxygen throughout the ischaemic period. During the 60 minutes of ischaemia, the lungs and the perfusate were kept at 370C.
Reperfusion after ischaemic interval was started slowly and the flow rate was increased such that a mean pulmonary arterial pressure (Pa) of 14 mm Hg was not exceeded. Within 5 minutes of the onset of the reperfusion the perfusate flow was increased to the same flow rate present before the ischaemic period (0.05ml/min/gm b.w.). During reperfusion, the perfusate reservoir and the lungs were maintained at 370C. Lungs were reperfused for 10min.
Three experimental groups were studied. The first group of 6 lungs underwent 60 minutes of ischaemia followed by 10 minutes of reperfusion. Same protocol was maintained for the Second group (n=6) with the exception that lidocaine at 5mg/Kg b.w. was added to the perfusate. This dose was calculated taking the blood volume at 8% of the body weight (50 ml blood volume for a rat). The third group served as control and underwent no ischaemia. The drug was added to the lung perfusate at the onset of lung perfusion prior to ischaemia.
At the end of each experiment the left main stem bronchus was transected and the left lung was isolated for the determination of the wet-to-dry lung weight ratio. Lungs were weighed and placed in a convection oven (Model 605, Precision Scientific Inc.) at 1200C and weighed daily for 3 days. Seventy two hours lung weight was reported as dry weight because after this time no further weight loss occurred. Mean pulmonary artery pressure (Pa) was measured for 10 minutes of pre-ischaemic period and the entire post-ischaemic period after the full flow was resumed. Percentage change was calculated taking the difference of the mean pre- and post-ischaemic pulmonary artery pressure. Mean peak airway pressure (Paw) was monitored for 10 minutes of pre-ischaemic period and the entire post-ischaemic period. Percent change was calculated taking the pre- and post-ischaemic pressure differences.
Values were expressed as mean ± SEM. Groups were compared using one way analysis of variance and the Tukey’s multiple comparison test using SAS statistical package.16
Lung weight remained stable in control lungs during the 70 minutes of perfusion. Lungs subjected to ischaemia and reperfusion had increased lung weight at the end of 10 minutes of reperfusion as recorded in the MacLab-4 (data not shown). Wet-to-dry weight ratio was significantly higher (p< 0.0001) in ischaemic reperfused lungs compared to that of the controls [Figure - 1]. Lungs subjected to ischaemia-reperfusion but treated with lidocaine at 5mg/kg b.w. had significantly lower wet-to-dry weight ratios (p < 0.0001) compared to untreated ischaemia-reperfused lungs [Figure - 1].
Pulmonary artery pressure (Pa) remained stable over the 70 minutes of perfusion in the control group of lungs not subjected to ischaemia. Lungs subjected to 60 min ischaemia reached a stable Pa within 10 minutes after the onset of reperfusion. The Pa was found to be significantly higher ( p < 0.0001) ten minutes after the onset of reperfusion, compared to the pressures observed in the same lung before ischaemia or compared to the Pa measured in the time-matched control lungs [Figure - 2]. The pulmonary artery pressure for control group, and ischaemia and lidocaine group before the onset of ischaemia are 13.22±3.95 (n=7), 12.96±2.98 (n=8) and 12.84±1.94 (n=7) of mmHg respectively. The Pa remained elevated compared to pre-ischaemic values in the same lung at 10 minutes after the onset of reperfusion. Lidocaine treatment (5mg/kg b.w.) significantly attenuated (p < 0.0001) the increase in the Pa pressure observed in post -ischaemic O2 ventilated reperfused lungs [Figure - 2].
Peak airway pressure (Paw) remained stable over 70 minutes of perfusion in the control group. In lungs subjected to 60 min ischaemia, Paw was significantly higher [Figure - 3] at 10 minutes of reperfusion. There was no difference in Paw of control lungs and lungs subjected to ischaemia-reperfusion but treated with 5mg/kg b.w. lidocaine [Figure - 3].
A major source of tissue damage in post-ischaemic reperfusion is believed to be the generation of oxygen-free radicals, and other toxic oxygen metabolite.[17],[18],[19] These radicals and metabolites have been implicated in post-ischaemic reperfusion injury in the heart, kidney, intestine, brain and other organs.[20],[21],[22],[23] Studies in the post-ischaemic-reperfusion injury in the lungs also implicate toxic oxygen metabolite as a source of damage.[2],[3],[8],[17] In our present study, lidocaine at 5mg/kg b.w. significantly reduced pulmonary oedema, pulmonary arterial pressure and peak air way pressure. Although lidocaine has numerous systemic and local effects on various biological tissues, both in vivo and in vitro,[24],[25] their ability to ameliorate post-ischaemic reperfusion injury in the lungs have not been previously recognized. We have demonstrated earlier that lidocaine is a hydroxyl radical scavenger, and inhibits NADPH-dependent lipid peroxidation in bovine lung microsomes.[15] Fox et al.[26] and Martin et al.[27] have demonstrated decreased lung injury by pre-treating the tissue with several scavengers, of reactive oxygen metabolites including DMSO, DMTU, SOD, catalase, and ethanol suggesting a prominent role for oxygen metabolites in lung injury. Kennedy et al.[28] have shown that ischaemia-reperfusion injury can be prevented by SOD, catalase or an iron chelator, desferrioxamine, suggesting that iron-mediated Fenton reaction may be required for the injury to occur. In O2 ventilated lung there is an increase in the production of lipid peroxides.[6] This increase is dependent on the percent of O2 in the inspired gas during ventilation in the ischaemic period.[6] In rat intestine, using salicylate as a radical trap, increased production of hydroxyl radicals have also been demonstrated during ischaemia.[29] Therefore, it is likely that tissue damage, such as membrane lipid peroxidation, observed during the reperfusion of ischaemic lungs was due to the production of these reactive metabolites.
The mechanism’ by which lidocaine afforded protection against reperfusion injury, may be explained, in part, by its antioxidant properties. We have found that lidocaine is a powerful hydroxyl radical scavenger, and inhibits lipid peroxidation in bovine lung microsomes.[15] Lidocaine was found to protect lungs against thiourea-induced lung injury in rats,[12] and was found to decrease the release of conjugated diene, a lipid peroxidation product in a canine myocardial ischaemia-reperfusion model.[13] The octanol:water partition coefficient for lidocaine is 2.39±0.10.[30] Therefore it is likely that lidocaine can exert its protective effect by removing lipid alkyl radicals. Our previous report demonstrating increased production of prostacyclines and thromboxane suggests that reperfusion of lung tissue may generate reactive oxygen forms.[31] While it is likely that lidocaine protects pulmonary tissue against O2 ventilated reperfusion injury by scavenging toxic Hydroxyl radicals. This can be very speculative and further studies are warranted to conclusively determine the protective effects of lidocaine.
The work reported herein was supported, in part, by grant HL42009 from the National Institute of Health, Bethesda, Maryland.
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Figures
[Figure - 1], [Figure - 2], [Figure - 3]
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