Burn-induced intestinal barrier failure has been proposed to be a potential cause of subsequent multiple organ failure after burn. Studies have shown that the increased iNOS activity is closely related to intestinal and pulmonary damage in rats after burn. Expression of iNOS and MMP-9 is regulated by nuclear factor NF-£eB activation, which is frequently a result of MAPKs pathway activation. This study was to investigate the role of ERKs in intestinal and pulmonary damage induced by burn in rats. In experiments, SD rats underwent 30 ~ 35 % TBSA burn. At various times after burn, intestinal mucosa and pulmonary proteins were assayed for ERKs and p38 phosphorylation by immunoblotting, nuclear extracts were assayed for NF-£eB activation by EMSA, intestinal and pulmonary iNOS, MMP-9 expressions were evaluated by RT-PCR, the FITC-dextran permeability was determined to assess the intestinal barrier function and the pulmonary microvascular dysfunction was quantitated by measuring the extravasation of Evans blue dye. The results show that burn induced ERKs and p38 phosphorylation, the expression of iNOS, and NF-£eB activation in intestinal mucosa and lung, but the expression of MMP-9 was attenuated. Treatment with MEK1/2 inhibitors, PD98059 (10 mg/kg i.p.) or U0126 (5 mg/kg i.p.) immediately after burn, attenuated the phosphorylation of intestinal mucosa and pulmonary ERKs, the activation of NF-£eB, the increase in intestinal permeability, and pulmonary microvascular dysfunction. Interestingly, the expression of iNOS in intestinal mucosa and pulmonary tissues was induced by PD98059 administration, but the expression of MMP-9 in intestinal mucosa was attenuated by PD98059 administration. These results suggest that the tissue damage is regulated by NF-£eB activation and the activation of NF-£eB is primarily mediated by signal pathway of ERKs in burn-injured rats, so the signal transduction pathway may involve ERKs and p38, NF-£eB, iNOS or MMP-9, then causes tissue damage. Further, burn-induced intestinal mucosa and pulmonary ERKs have different degree of activation. The p38 and ERKs phosphorylation showed a two-step activation in intestinal mucosa and pulmonary tissues after burn. Inhibition of intestinal and pulmonary ERKs in vivo afforded significant protection against burn-induced barrier failure. However, the data showed that iNOS may not play a major role in the burn-induced intestinal and pulmonary damage, and MMP-9 may have more affect on tissues damage.