The Roles Of HO-1/CO In CCK-8 Attenuating Acute Lung Injury Induced By LPS

Lipopolysaccharide (LPS) . the main component of Gram-negative bacterial endotoxin, is the main factor to induce endotoxin shock (ES). ES is a common and severe pathological process with high mortality in clinical practice. Lung is one of the target organs primarily impaired in the early stage of ES. Pulmonary artery hypertension (PAH) is the typical pathological change in the early phase of ES. It was reported that the degree and duration of PAH were important factors of ES accompanied by acute lung injury (ALI). Pulmonary artery smooth muscle cell (PASMC) played an important role in maintaining the tone of pulmonary artery during ES. Previous studies demonstrated that many inflammatory substances such as inflammatory cytokines, oxygen free radicals (OFR) and nitric oxide (NO) and so on played major roles in the process of ALI during ES. There was a rapid increase in anti-oxidative substances such as heme oxygenase-1 (HO-1) and cholecystokinin (CCK) that provided protection against oxidative injury during ES. HO-1 is a novel stress protein. It can be induced by many factors that could induce oxidative injury. It was demonstrated by the studies of Zhou JL et al in our laboratory that HO-1 and its metabolic product-carbon monoxide (CO) had protective effects during ALI induced by ischemia/refusion (I/R) of limb. It has been well documented that CCK, a kind of brain-gut peptide, is involved in many physiological and pathophysiological processes. Sulfated cholecystokinin-octapeptide (CCK-8) is the minimum sequence for biological activity. It was well known that the actions of CCK are mainly mediated by two distinct receptors, CCK-A receptor (CCK-AR) and CCK-B receptor (CCK-BR). Particular emphasis had been laid on its regulatory actions in nervous system, digestive system, and endocrine system in the previous studies of CCK. CCK is also demonstrated to be located in thelung. However, reports about the effects of CCK-8 on the lung especially on the pathophysical changes of the lung during ES were seldom seen. The serial studies of our laboratory demonstrated that CCK-8 had protective actions against ES, and could partly reverse the increase of pulmonary artery pressure as well as attenuate the lung injury induced by LPS. The results of previous studies showed that there maybe exist internal relationship among the above-mentioned protective actions of CCK-8, HO-1 and its product-carbon monoxide (CO).The mitogen-activated protein kinase (MAPK) family is the cross point of discrete signaling cascades for diverse extracellular stimuli, and function to regulate fundamental cellular processes. Four distinct subfamilies have been described in enkaryocyte: extracellular-signal regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), p38MAPK and ERK5/BMK, (big mitogen-activated protein kinase). JNK, also called as stress-activated protein kinase (SAPK), which can be activated by various stressors, proinflammatory cytokines and inflammatory mediators, played an important role in oxidative stress response when it was activated. It was well known that LPS could activate MAPK signal pathway. CCK-8 has been demonstrated to have the similar role in pancreas acinus cell. Transcription factors are the important targets of MAPK. Activator protein-1(AP-1), the first identified transcription factor, played an important role in anti-inflammation response. Many experiments showed that AP-1 was very important in HO-1 regulation. AP-1 is not a single protein, but a dimmer consisted of many kinds protein with leucine zippers domain. Among its components, c-Jun is the one with the strongest action. Only when c-Jun was sustained expressed and phosphorylated meanwhile, could the expression of HO-1 be induced. It was verified that JNK was an important factor to regulate the phosphorylation of c-Jun as well as the only protein kinase to effectively phosphorylate Ser-63 and Ser-73 of c-Jun in MAPK family. From the above, we supposed that JNK/c-Jun signal pathway was invovled in the expression of HO-1 induced by LPS.12However, it hadn't bee...