Lee Hui Su, Kim Hee Jae, Moon Chang Sook, Chong Young Hae, Kang Jihee Lee
Department of Physiology, Division of Cell Biology, Ewha Medical Research Institute, Ewha Womans University College of Medicine, 911-1 Mok-6-dong, Yangcheon-ku, Seoul 158-056, Korea.
Respir Res. 2004 Nov 27;5(1):23. doi: 10.1186/1465-9921-5-23.
Although in vitro studies have determined that the activation of mitogen-activated protein (MAP) kinases is crucial to the activation of transcription factors and regulation of the production of proinflammatory mediators, the roles of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in acute lung injury have not been elucidated.
Saline or lipopolysaccharide (LPS, 6 mg/kg of body weight) was administered intratracheally with a 1-hour pretreatment with SP600125 (a JNK inhibitor; 30 mg/kg, IO), or PD98059 (an MEK/ERK inhibitor; 30 mg/kg, IO). Rats were sacrificed 4 hours after LPS treatment.
SP600125 or PD98059 inhibited LPS-induced phosphorylation of JNK and ERK, total protein and LDH activity in BAL fluid, and neutrophil influx into the lungs. In addition, these MAP kinase inhibitors substantially reduced LPS-induced production of inflammatory mediators, such as CINC, MMP-9, and nitric oxide. Inhibition of JNK correlated with suppression of NF-kappaB activation through downregulation of phosphorylation and degradation of IkappaB-alpha, while ERK inhibition only slightly influenced the NF-kappaB pathway.
JNK and ERK play pivotal roles in LPS-induced acute lung injury. Therefore, inhibition of JNK or ERK activity has potential as an effective therapeutic strategy in interventions of inflammatory cascade-associated lung injury.
尽管体外研究已确定丝裂原活化蛋白（MAP）激酶的激活对于转录因子的激活和促炎介质产生的调节至关重要，但c-Jun氨基末端激酶（JNK）和细胞外信号调节激酶（ERK）在急性肺损伤中的作用尚未阐明。
经气管内给予生理盐水或脂多糖（LPS，6mg/kg体重），并预先用SP600125（一种JNK抑制剂；30mg/kg，腹腔注射）或PD98059（一种MEK/ERK抑制剂；30mg/kg，腹腔注射）预处理1小时。LPS处理4小时后处死大鼠。
SP600125或PD98059抑制LPS诱导的JNK和ERK磷酸化、BAL液中的总蛋白和LDH活性以及中性粒细胞向肺内的流入。此外，这些MAP激酶抑制剂显著降低了LPS诱导的炎症介质如CINC、MMP-9和一氧化氮的产生。JNK的抑制与通过下调IκB-α的磷酸化和降解来抑制NF-κB活化相关，而ERK的抑制仅对NF-κB途径有轻微影响。
JNK和ERK在LPS诱导的急性肺损伤中起关键作用。因此，抑制JNK或ERK活性在干预炎症级联相关的肺损伤方面具有作为有效治疗策略的潜力。
