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Protective effects of cromolyn sodium on intestinal ischaemia-reperfusion-triggered lung injury in rats

2007; Elsevier BV; Volume: 98; Issue: 3 Linguagem: Inglês

10.1093/bja/ael383

1471-6771

Ziqing Hei, Xiaoliang Gan, Hongyan Huang, G.-J. Luo, shengcun li, Jing Cai,

Sulfur Compounds in Biology

Editor—Intestinal ischaemia-reperfusion (IR) injury is recognized clinically.1Waisman D Brod V Wolff R et al.Effects of hyperoxia on local and remote microcirculatory inflammatory response after splanchnic ischemia and reperfusion.Am J Physiol Heart Circ Physiol. 2005; 285: H643-H652Crossref Scopus (54) Google Scholar The mechanism of lung injury induced by intestinal IR is complex. Both Giakoustidis and colleagues2Giakoustidis AE Giakoustidis DE Iliadis S et al.Attenuation of intestinal ischemia/reperfusion induced liver and lung injury by intraperitoneal administration of (−)-epigallocatechin-3-gallate.Free Radic Res. 2006; 40: 103-110Crossref PubMed Scopus (41) Google Scholar and Ito and colleagues3Ito K Ozasa H Horikawa S Edaravone protects against lung injury induced by intestinal ischemia/reperfusion in rat.Free Radic Biol Med. 2005; 38: 369-374Crossref PubMed Scopus (48) Google Scholar found that malondialdehyde (MDA) content in lung increased significantly and superoxide dismutase (SOD) activity in lung decreased significantly after intestinal IR and could be attenuated with antioxidant drug treatment. Mukundan and colleagues4Mukundan C Gurish MF Austen KF Hechtman HB Friend DS Mast cell mediation of muscle pulmonary injury following hindlimb ischemia-reperfusion.J Histochem Cytochem. 2001; 49: 1055-1056Crossref PubMed Scopus (24) Google Scholar found that mast cells (MC) in lung-derived chymase mMCP-1 coated alveolar macrophages after hindlimb IR and induced direct lung injury. Cromolyn sodium can stabilize the MC membrane, thereby inhibiting mediator release,5Neffen HE Pharmaco-prevention of bronchial ashma using membrane stabilizers and asthma mortality.Rev Alerg Mex. 1990; 37: 155-163PubMed Google Scholar and has a direct scavenging effect on reactive oxygen species.6Sadeghi-Hashjin G Nijkamp FP Henricks PAJ Folkerts G Sodium cromoglycate and doxantrazole are oxygen radical scavengers.Eur Respir J. 2002; 20: 867-872Crossref PubMed Scopus (14) Google Scholar We hypothesize that MC degranulation may be associated with lung injury after intestinal IR. The focus of our study was the protective effects of cromolyn sodium on intestinal IR-triggered lung injury in rats and its mechanism of action. Our pilot study included 32 Sprague–Dawley rats randomly allocated to four groups: sham-operated, model, high-dosage (treated with cromolyn sodium 50 mg kg−1) and low-dosage (cromolyn sodium 25 mg kg−1) groups. Intestinal damage was induced by clamping the superior mesenteric artery for 45 min and then reperfusion for 60 min. Cromolyn sodium was given by i.p. injection 15 min before reperfusion. After reperfusion, the lungs were removed immediately for the determination of lung water content [(wet weight–dry weight)/wet weight × 100%], lung MDA contents, SOD activity, lung permeability index (bronchoalveolar lavage fluid protein concentration/serum protein concentration), lung histamine concentration, and lung histology assay and MC counts (Table 1).Table 1Changes in pathological score, mast cell counts, permeability index, water content, MDA content, SOD activity, and histamine concentration in lung in various groups [mean (sd)]GroupnPulmonary pathological scorePulmonary mast cell counts (n field−1)Lung permeability index (×100%)Lung water content (×100%)SOD (U mg−1)MDA (nmol g−1)Histamine (ng mg−1)Sham-operated80.63 ± (0.52)2.1 ± (0.6)4.19 ± (2.92)76.39 ± (1.72)372.4 ± (29.0)2.3 ± (0.3)0.22 ± (0.12)Model83.25 ± (0.46)**2.5 ± (0.8)9.90 ± (4.33)*83.74 ± (3.82)*259.5 ± (23.0)*4.2 ± (0.6)**0.17 ± (0.05)High dosage81.75 ± (0.46)**##2.2 ± (0.5)6.26 ± (3.18)78.89 ± (1.97)#325.9 ± (14.4)*3.3 ± (0.6)**##0.21 ± (0.07)Low dosage82.50 ± (0.53)**##ΔΔ2.4 ± (0.5)7.69 ± (2.81)79.28 ± (1.82)*331.9 ± (27.8)*3.5 ± (0.7)**#0.23 ± (0.05)*P < 0.05, **P < 0.01 vs sham-operated group; #P < 0.05,##P < 0.01 vs model group; ΔP < 0.05, ΔΔP < 0.01 vs low-dosage group. Open table in a new tab *P < 0.05, **P < 0.01 vs sham-operated group; #P < 0.05,##P < 0.01 vs model group; ΔP < 0.05, ΔΔP < 0.01 vs low-dosage group. The major findings of our study were that MDA content was increased and SOD activity decreased remarkably in model group. Pretreatment with cromolyn sodium attenuated the upregulation of MDA content and the downregulation of SOD activity. The lung injury score was positively correlated with MDA content, whereas negatively correlated with SOD activity in the four studied groups. Lung water content and lung permeability index of model group were increased significantly compared with that of the sham-operated group. However, there was no significant difference in MC count and histamine concentration among the four groups. The results were different from that of Kasaka and colleagues,7Kasacka I Humenczk M Niczyporuk M Mycko G The evaluation of murine pleural lavage fluid cellular composition in experimental hemorrhagic shock with special regard to mast cells morphometry.J Physiol Pharmacol. 2001; 52: 293-301PubMed Google Scholar but we propose that different animal models may produce different results, and this hypothesis need further investigation. Our data provide evidence that cromolyn sodium demonstrates protective effects in vivo on IR-triggered lung injury in rats without a change in MC counts or histamine concentration. Downregulation of MDA content and upregulation of SOD activity may be an important mechanism of action. Further studies are necessary to measure tryptase level.