Acute Pancreatitis-associated Lung Injury Research Articles

Captopril pretreatment protects the lung against severe acute pancreatitis induced injury via inhibiting angiotensin II production and suppressing Rho/ROCK pathway

Acute pancreatitis (AP) usually causes acute lung injury, which is also known as acute pancreatitis associated lung injury (APALI). This study aimed to investigate whether captopril pretreatment was able to protect lung against APALI via inhibiting angiotensin II (Ang II) production and suppressing Rho/ROCK (Rho kinase) pathway in rats. Severe AP (SAP) was introduced to rats by bile–pancreatic duct retrograde injection of 5% sodium taurocholate. Rats were randomly divided into three groups. In the sham group, sham operation was performed; in the SAP group, SAP was introduced; in the pre-cpl + SAP group, rats were intragastrically injected with 5 mg/kg captopril 1 hour prior to SAP induction. Pathological examination of the lung and pancreas, evaluation of pulmonary vascular permeability by wet/dry ratio and Evans Blue staining, detection of serum amylase, Western blot assay for Ang II receptor type 1 (AT1), RhoA, ROCK (Rho kinase), and MLCK (myosin light chain kinase) were performed after the animals were sacrificed at 24 hours. After the surgery, characteristic findings of pancreatitis were observed, accompanied by lung injury. The serum amylase, Ang II, and lung expression of AT1, RhoA, ROCK, and MLCK increased dramatically in SAP rats. However, captopril pretreatment improved the histological changes, reduced the pathological score of the pancreas and lung, inhibited serum amylase and Ang II production, and decreased expression of AT1, RhoA, ROCK, and MLCK in the lung. These findings suggest that captopril pretreatment is able to protect the lung against APALI, which is, at least partially, related to the inhibition of Ang II production and the suppression of the Rho/ROCK pathway.

Caspase inhibitor zVAD-fmk protects against acute pancreatitis-associated lung injury via inhibiting inflammation and apoptosis

Background/objectivesPulmonary apoptosis is an important pathogenic mechanism of acute lung injury induced by many factors. This study aims to investigate whether the caspase inhibitor zVAD-fmk has a protective effect against lung injury in the severe acute pancreatitis model (SAP) in rats. MethodsSeventy-two Sprague-Dawley rats were randomly divided into Sham, SAP, and SAP + zVAD-fmk groups. The SAP model was established by injection of 5% sodium taurocholate into the pancreatic duct. Animals were sacrificed at 3 h, 6 h, 12 h, and 24 h after operation and then HE staining analysis was performed to assess the lung injury. ELISA was used to detect the activity of myeloperoxidase (MPO) and the concentrations of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Western blotting was used to detect the expression of cleaved caspase-3 in the lung tissues. ResultsRats in SAP group showed obvious lung injury through pathologic examination. Pretreatment with zVAD-fmk significantly inhibited a post-SAP increase in the activation of MPO, TNF-α, IL-1β, and caspase-3, and decreased lung injury induced by SAP as determined by the pathologic score. ConclusionOur results suggest that apoptosis plays an important role in acute pancreatitis-associated lung injury (APALI), and inhibition of caspase activity may represent a new therapeutic approach for the treatment of APALI.

Effects of Nicotine and Vagus Nerve in Severe Acute Pancreatitis-Associated Lung Injury in Rats.

The cholinergic anti-inflammatory pathway has been elucidated as a regulator of inflammatory responses in several experimental models of diseases. This regulatory mechanism is mediated by acetylcholine, released from efferent vagus nerve, interacts with α7 nicotinic acetylcholine receptors on immune cells. Experimental evidence indicates that vagus nerve stimulation or α7 nicotinic acetylcholine receptor agonists control proinflammatory cytokine production and protect animals in diverse lethal models. The aim of the study was to investigate effect of the cholinergic anti-inflammatory pathway in acute lung injury in an experimental model of severe acute pancreatitis (SAP). In taurocholate-induced SAP in rats, pancreatitis was preceded by pretreatment with the nicotinic receptor agonist nicotine or unilateral left cervical vagotomy. Pretreatment with nicotine strongly alleviated severity of SAP-associated lung injury through attenuating serum amylase, lipase, and interleukin 6 levels; pancreas and lung pathological injury; lung myeloperoxidase activity; lung tumor necrosis factor-α; and high-mobility group box 1 expression. Inversely, vagotomy pretreatment resulted in an enhanced severity of pancreatitis and lung injury. Our results reveal the role of the cholinergic anti-inflammatory pathway in experimental SAP-associated lung injury; nicotine pretreatment exerts a protective effect and vagotomy pretreatment exerts the opposite effect.

Reverse-migrated neutrophils regulated by JAM-C are involved in acute pancreatitis-associated lung injury.

Junctional adhesion molecule-C (JAM-C) plays a key role in the promotion of the reverse transendothelial migration (rTEM) of neutrophils, which contributes to the dissemination of systemic inflammation and to secondary organ damage. During acute pancreatitis (AP), systemic inflammatory responses lead to distant organ damage and typically result in acute lung injury (ALI). Here, we investigated the role of rTEM neutrophils in AP-associated ALI and the molecular mechanisms by which JAM-C regulates neutrophil rTEM in this disorder. In this study, rTEM neutrophils were identified in the peripheral blood both in murine model of AP and human patients with AP, which elevated with increased severity of lung injury. Pancreatic JAM-C was downregulated during murine experimental pancreatitis, whose expression levels were inversely correlated with both increased neutrophil rTEM and severity of lung injury. Knockout of JAM-C resulted in more severe lung injury and systemic inflammation. Significantly greater numbers of rTEM neutrophils were present both in the circulation and pulmonary vascular washout in JAM-C knockout mice with AP. This study demonstrates that during AP, neutrophils that are recruited to the pancreas may migrate back into the circulation and then contribute to ALI. JAM-C downregulation may contribute to AP-associated ALI via promoting neutrophil rTEM.

Dihydro-Resveratrol Ameliorates Lung Injury in Rats with Cerulein-Induced Acute Pancreatitis.

Acute pancreatitis is an inflammatory process originated in the pancreas; however, it often leads to systemic complications that affect distant organs. Acute respiratory distress syndrome is indeed the predominant cause of death in patients with severe acute pancreatitis. In this study, we aimed to delineate the ameliorative effect of dihydro-resveratrol, a prominent analog of trans-resveratrol, against acute pancreatitis-associated lung injury and the underlying molecular actions. Acute pancreatitis was induced in rats with repetitive injections of cerulein (50 µg/kg/h) and a shot of lipopolysaccharide (7.5 mg/kg). By means of histological examination and biochemical assays, the severity of lung injury was assessed in the aspects of tissue damages, myeloperoxidase activity, and levels of pro-inflammatory cytokines. When treated with dihydro-resveratrol, pulmonary architectural distortion, hemorrhage, interstitial edema, and alveolar thickening were significantly reduced in rats with acute pancreatitis. In addition, the production of pro-inflammatory cytokines and the activity of myeloperoxidase in pulmonary tissues were notably repressed. Importantly, nuclear factor-kappaB (NF-κB) activation was attenuated. This study is the first to report the oral administration of dihydro-resveratrol ameliorated acute pancreatitis-associated lung injury via an inhibitory modulation of pro-inflammatory response, which was associated with a suppression of the NF-κB signaling pathway.

Enhancement of ICAM-1 via the JAK2/STAT3 signaling pathway in a rat model of severe acute pancreatitis-associated lung injury.

Acute lung injury (ALI), which is associated with severe acute pancreatitis (SAP), results from damage to the pulmonary microvascular endothelial cells (PMVECs), which in turn leads to high levels of inflammatory cytokines that destroy PMVECs. However, the molecular mechanisms underlying SAP-associated ALI (SAP-ALI) are currently not well understood. Intercellular adhesion molecule-1 (ICAM-1) has been implicated in the persistent migration and accumulation of neutrophils and macrophages, which in turn has been associated with the increased permeability of microvascular endothelial cells. Signal transduction via the Janus kinase-2 (JAK2)/signal transducer and activator of transcription-3 (STAT3) transcription factors has been shown to be involved in inflammation. The present study aimed to investigate the expression levels of ICAM-1 and JAK2/STAT3 signaling components in a rat model of SAP-ALI. SAP was induced in the rat model, and dexamethasone (DEX) was administered to the treatment group. Subsequently, ICAM-1, interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, JAK2, STAT3 and nuclear factor (NF)-κB mRNA expression levels were determined using reverse transcription-polymerase chain reaction; ICAM-1 protein expression levels were determined using western blotting; and IL-6, IL-8 and TNF-α levels were measured via an enzyme-linked immunosorbent assay. In addition, an immunohistochemical analysis of ICAM-1, NF-κB, JAK2 and STAT3 was conducted, and the protein expression and cell morphology of the lungs in all rats was analyzed. ICAM-1 mRNA and protein expression levels were significantly increased following induction of SAP, and were significantly decreased in the DEX-treated group. Furthermore, treatment with DEX significantly reduced serum expression levels of IL-6, IL-8 and TNF-α and decreased expression levels of NF-κB, JAK2 and STAT3 in the lung tissue, as compared with the untreated SAP group. The present study demonstrated that DEX treatment was able to suppress ICAM-1 mRNA and protein expression in a rat model of SAP-ALI via the inhibition of IL-6 and TNF-α-induced JAK2/STAT3 activation; thus suggesting that DEX treatment may be considered a potential strategy in the treatment of patients with SAP-ALI.

Protective mechanism of sivelestat on acute necrotizing pancreatitis-associated acute lung injury in rats

Protective mechanism of sivelestat on acute necrotizing pancreatitis-associated acute lung injury in rats

Tyrosine protein kinase Tec is involved in the pathogenesis of severe acute pancreatitis associated lung injury in mice

s / Pancreatology 16 (2016) S1eS63 S20 tumors and in forming diagnostic and surgical strategies to reduce the post operative complication.

Apigenin Attenuates Inflammation in Experimentally Induced Acute Pancreatitis-Associated Lung Injury

ABSTRACTBackground: Acute pancreatitis is associated with acute lung injury. The aim of the present study is to evaluate alterations of lungs in an experimental model of acute pancreatitis (AP) following both bilio-pancreatic duct obstruction close to the duodenum. Acute pancreatitis is a common disease with significant mortality. This situation makes the need of finding protective factors for the lung parenchyma, imperative. In the present study there is an effort to clarify the role of apigenin, a substance which is well known for its antioxidant and anti-inflammatory effects, on lung injury, following acute pancreatitis in rats. Materials and methods: In the present study, 126 male Wistar-type rats 3–4 months old and 220–350 g weight were used. At time 0 we randomly assigned the following groups: Group Sham: Rats were subjected to virtual surgery. Group Control: Rats were subjected to surgery for induction of acute pancreatitis. Group Apigenin: Rats were subjected to surgery for induction of acute pancreatitis and enteral feeding with apigenin. Immunochemistry for TNF-α and IL-6 as well as MPO activity were measured at predetermined time intervals 6, 12, 24, 48, and 72 h, in order to evaluate architectural disturbances of the lung tissue. Results: From the pathological reports we realized that comparing the control group with the apigenin group, there is an improvement of lung tissue damage following apigenin administration, with statistical significance. Apigenin reduces most histopathological alterations of the pulmonary tissue, reduces MPO and TNF-α activity at 48 hours and, furthermore, reduces IL-6 activity at 72 hours post-administration. Conclusions: Oral Apigenin administration in rats, following experimental induced acute pancreatitis, seems to be protective on the lung tissue. Apigenin administration to humans could potentially ameliorate acute lung injuries. However, special caution is required for humans' use, as more detailed studies are needed.

Research progress of systemic inflammatory response syndrome in acute pancreatitis-associated lung injury

As a result of the early amplification of the inflammatory response in the acute pancreatitis, systemic inflammatory response syndrome (SIRS) is a main cause of acute pancreatitis-associated lung injury (APALI), while early combined acute lung injury or acute respiratory distress syndrome causes a high mortality of acute pancreatitis. A series of inflammatory mediators and cytokines play important roles in the process of SIRS and APALI, therefore, inflammatory reaction restoring a balance becomes a key point of the treatment of pancreatitis lung injury. Key words: Acute pancreatitis; Acute lung injury; Systemic inflammatory response syndrome

Ultrastructural changes in the pulmonary mechanical barriers in a rat model of severe acute pancreatitis-associated acute lung injury

ABSTRACTThis study examined the ultrastructural changes in the pulmonary mechanical barriers in a rat model of severe acute pancreatitis (SAP)-associated acute lung injury (ALI). Animals were randomized into the SAP group (n = 60) and the control group (n = 60). SAP was induced by retrograde injection of 5% taurocholic acid into the biliopancreatic duct. The morphological abnormalities assessed by histology and the lung wet/dry weight ratio and the ultrastructural abnormalities assessed by transmission electron microscope and scanning electron microscope examinations plus lanthanum nitrate tracing were compared between the two groups at 6, 12, and 24 h post-SAP induction (n = 10/group/time point). The SAP group had significantly greater extravascular effusion than the control group at each time point as assessed by the lung wet/dry weight ratio (p < .001). The severity of the tissue damage increased in the lung and pancreas over time in the SAP group (all p < .001). In the SAP group, ultrastructural damages to the endothelial, epithelial, and pleural barriers were apparent and the damages to the endothelial barrier were detected earlier than the other two barriers, suggesting its fundamental role in preventing the further development of SAP-associated ALI. Moreover, the ultrastructural abnormalities were detected earlier than symptoms and morphological changes. The ultrastructural damages in the endothelial, epithelial, and pleural barriers occurred in the early stage of SAP. The endothelial barrier is likely to be the first line to prevent the further development in this rat model of SAP-associated ALI.

Thalidomide Inhibits Adhesion Molecules in Experimental Acute Pancreatitis-Associated Lung Injury.

Preclinical Research The study evaluated the effect of thalidomide on adhesion molecule expression in acute pancreatitis-associated lung injury in rats. Acute pancreatitis was induced in rats by retrograde infusion of 5% sodium taurocholate into the bile-pancreatic duct, and thalidomide (100 mg/kg) was given daily by intragastric route for 8 days before this treatment. Serum lipase (LPS), protein levels in bronchoalveolar lavage fluid (BALF), superoxide dismutase (SOD), glutathione peroxidase (GSHpx), and malondialdehyde (MDA) levels in lung were measured. Compared with the acute pancreatitis- group, lung histopathology, serum LPS, protein levels in BALF, SOD, GSHpx, and MDA levels, and the expression levels of intercellular adhesion molecule-1 and E-selectin mRNA and protein in rats given thalidomide were improved (P < 0.01). Thus, thalidomide may reduce the expression of adhesion molecules via inhibition of oxidative stress to alleviate acute pancreatitis-associated lung injury in a rat model. Drug Dev Res, 2014. © 2014 Wiley Periodicals, Inc.

The association between red blood cell distribution width and acute pancreatitis associated lung injury in patients with acute pancreatitis.

BackgroundRed blood cell distribution width (RDW) that describes red blood cell volume heterogeneity is a common laboratory test. Our aim was to focus on the association between RDW and acute pancreatitis associated lung injury (APALI).MethodologyA total of 152 acute pancreatitis (AP) patients who conformed to the criteria were included in this study. The demographic data, medical histories and laboratory measures was obtained from each patient on admission, further, the medical histories and biological data were analyzed, retrospectively.ResultsIncreased RDW at admission was observed in patients with APALI compared with the non-APALI groups. Our results exhibited that RDW was an independent risk factor for APALI after adjusting leukocyte, neutrophil percentage, random blood glucose (RBG), total bilirubin (TB) and total bile acid (TBA) (Crude model) (OR=2.671;CI 95% 1.145–6.230; P=0.023), further adjustment based on Crude model for sex and age did not attenuate the significantly high risk of APALI in patients with AP, RWD still remained a roles as an independent risk factor for APALI (OR=2.653;CI95 % 1.123–6.138; P=0.026).ConclusionsOur study demonstrate that RDW at admission is associated with APALI and should be considered as an underlying risk factor of APALI.

Effects of hypoxia-inducible factor-1α and matrix metalloproteinase-9 on alveolar-capillary barrier disruption and lung edema in rat models of severe acute pancreatitis-associated lung injury

The aim of this study was to investigate the effects of hypoxia-inducible factor-1α (HIF-1α) and matrix metalloproteinase-9 (MMP-9) on alveolar-capillary barrier disruption and lung edema in rat models of severe acute pancreatitis-associated lung injury (PALI). A total of 40 male Sprague-Dawley rats were randomly divided into a sham surgery group (n=10) and three PALI groups, in which acute pancreatitis was induced by the retrograde infusion of 5% sodium taurocholate (1 ml/kg). The PALI groups were as follows: i) Untreated PALI group (n=10); ii) 2-methoxyestradiol (2ME2) group (5 mg/kg body mass; n=10); and iii) 2ME2 group (15 mg/kg body mass; n=10). In the two 2ME2 groups, the HIF-1α inhibitor 2ME2 was administered intraperitoneally 1 h after the induction of AP. The severity of the pancreatitis was evaluated by the serum amylase levels and pathology. The severity of the lung injury was evaluated by the wet/dry ratio, blood gas analysis and pathology. The alveolar-capillary barrier disruption was assessed by Evans blue dye extravasation. The protein and mRNA expression levels of HIF-1α and MMP-9 were studied using enzyme-linked immunosorbent assays (ELISAs), western blot analysis and reverse transcription-polymerase chain reaction. The active tumor necrosis factor-α levels were measured using an ELISA. The HIF-1α inhibitor 2ME2 attenuated the severity of the pancreatitis and PALI, while the lung edema and alveolar-capillary barrier disruption were significantly ameliorated compared with those in the untreated PALI group. Administration of the higher dose of 2ME2 significantly suppressed the protein expression of MMP-9 in the lung tissues. The results indicate that HIF-1α has a major function in alveolar-capillary barrier disruption and lung edema in PALI via a molecular pathway cascade involving MMP-9. Inhibition of HIF-1α by 2ME2 attenuates alveolar-capillary barrier disruption and lung edema. Pharmacological blockade of this pathway in patients with PALI may provide a novel therapeutic strategy.

Thalidomide alleviates acute pancreatitis-associated lung injury via down-regulation of NFκB induced TNF-α

AimsWe studied the effect of thalidomide on NFκB-induced TNF-α in acute pancreatitis-associated lung injury in the rat. MethodsRats were intragastrically administered thalidomide (100mg/kg) daily for 8 days and then acute pancreatitis was induced by retrograde infusion of 5% sodium taurocholate into the rat biliopancreatic duct. Serum amylase (AMY), blood oxygen partial pressure (PaO2), ratios of lung wet/dry weight, and cytoplasmic IκBα and TNF-α protein and nuclear NFκBp65 protein were measured. Also, lung NFκBp65 and TNF-α mRNA were measured. ResultsCompared with the model group, the pathological score of the pancreas and lung, serum AMY, ratios of lung wet/dry weight, and lung NFκBp65 and TNF-α mRNA and protein of rats given thalidomide were decreased significantly (P<0.01), but PaO2 and IκBα protein was elevated significantly (P<0.01). ConclusionThalidomide may inhibit TNF-α expression via down-regulation of the NFκB signaling pathway to alleviate acute pancreatitis-associated lung injury in rats.

Combined effects of sivelestat and resveratrol on severe acute pancreatitis-associated lung injury in rats

ABSTRACTDespite extensive research and clinical efforts made in the management of acute pancre­atitis during the past few decades, to date no effective cure is available and the mortality from severe acute pancre­atitis remains high. Given that lung is the primary cause of early death in acute pancreatitis patients, novel therapeutic approaches aiming to prevent lung injury have become a subject of intensive investigation. In a previous study, we demonstrated that sivelestat, a specific inhibitor of neutrophil elastase, is effective in protecting against lung failure in rats with taurocholate-induced acute pancreatitis. As part of the analyses extended from that study, the present study aimed to evaluate the role of sivelestat and/or resveratrol in the protection against acute pancreatitis-associated lung injury. The extended analyses demonstrated the following: (1) sodium taurocholate induced apparent lung injury and dysfunction manifested by histological anomalies, including vacuolization and apoptosis of the cells in the lung, as well as biochemical aberrations in the blood (an increase in amylase concentration and a decrease in partial arterial oxygen pressure) and increases in activities of reactive oxygen species, interleukin 6, myeloperoxidase, neutrophil elastase, lung edema, bronchotracho alveolar lavage protein concentration, and bronchotracho alveolar lavage cell infiltration in the lung; and (2) in lung tissues, either sivelestat or resveratrol treatment effectively attenuated the taurocholate-induced abnormalities in all parameters analyzed except for serum amylase concentration. In addition, combined treatment with both sivelestat and resveratrol demonstrated additive protective effects on pancreatitis-associated lung injury compared with single treatment.

Protective Effects of BML-111 on Cerulein-Induced Acute Pancreatitis-Associated Lung Injury via Activation of Nrf2/ARE Signaling Pathway

The aim of this study was to investigate whether BML-111 can exert protective effects on cerulein-induced acute pancreatitis-associated lung injury (APALI) via activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant responsive element (ARE) signaling pathway. Severe acute pancreatitis (SAP) was established by intraperitoneal injection of cerulein (50μg/kg) seven times at hourly intervals and Escherichia coli lipopolysaccharide (10mg/kg) once after the last dose of cerulein immediately. BML-111 (1mg/kg) was administered 1h before the first injection of cerulein. Samples were taken at 3, 6, 12, and 24h after the last injection. Pathologic lesions of the pancreas and lung tissues as well as the levels of serum amylase were analyzed; Myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), Nrf2, heme oxygenase-1 (HO-1), and quinone oxidoreductase-1 (NQO1) of lung tissue were determined. The findings revealed that the injuries of pancreas and lung were typically induced by cerulein. The administration of BML-111 reduced the levels of serum amylase, lung MPO, lung MDA, the wet-to-dry weight ratio, and the pathology injury scores of the lung and pancreas, which increased in the SAP group. The expressions of Nrf2, HO-1, NQO1, and activity of SOD in lung tissue increased in the BML-111 group compared with those in the SAP group. This study indicates that BML-111 may play a critical protective role in APALI induced by cerulein. The underlying mechanisms of protective role may be attributable to its antioxidant effects through the activation of Nrf2/ARE pathway.

Treatment with ginkgo biloba extract protects rats against acute pancreatitis-associated lung injury by modulating alveolar macrophage.

IntroductionAcute pancreatitis (AP) protease release induces lung parenchymal destruction via inflammatory mediators. Ginkgo biloba has been reported to have anti-inflammatory effects.AimTo evaluate the effect of ginkgo biloba extract on experimental acute pancreatitis-associated lung injury in the rat and to investigate the underlying mechanisms.Material and methodsAcute pancreatitis was induced in rats by injection of 5% sodium taurocholate into the biliary pancreatic duct. Ginkgo biloba extract (GBE) was administered and pancreas and lung injury were assessed by histological examination. Alveolar macrophages were harvested by bronchoalveolar lavage. Specificity fluorescent probe DAF-FM-DA was applied to observe nitric oxide (NO) bioavailability in alveolar macrophage. The expression of tumour necrosis factor α (TNF-α) and macrophage migration inhibitory factor (MIF) protein in alveolar macrophage was studied by ELISA.ResultsIn sodium taurocholate-induced acute pancreatitis, treatment with GBE significantly protected rats against lung injury associated with pancreatitis in histological sections. Ginkgo biloba extract had a tendency to down-regulate NO bioavailability compared with the AP group, but without statistical significance. Moreover, TNF-α and MIF at protein levels in alveolar macrophage with GBE treatment were decreased compared with the AP group.ConclusionsThese results suggest that GBE could effectively protect rats against acute pancreatitis-associated lung injury. The GBE may inhibit excessive activation of alveolar macrophages from acute pancreatitis-associated lung injury through down-regulation of generation of NO, TNF-α and MIF. These findings suggest that ginkgo biloba extract is a suitable candidate as an effective strategy against acute pancreatitis-associated lung injury.

Cystathionine-gamma-lyase inhibitor attenuates acute lung injury induced by acute pancreatitis in rats.

IntroductionAcute pancreatitis (AP) is known to induce injuries to extrapancreatic organs. Because respiratory dysfunction is the main cause of death in patients with severe AP, acute pancreatitis-associated lung injury (APALI) is a great challenge for clinicians. This study aimed to investigate the potential role of hydrogen sulfide (H2S) in the pathogenesis of APALI.Material and methodsFifty-four SD rats were randomly divided into three groups: the AP group of rats that received injection of sodium deoxycholate into the common bile duct, the control group that underwent a sham operation, and the treatment group made by intraperitoneal injection of propargylglycine (PAG), an inhibitor of cystathionine-γ-lyase (CSE), into rats with AP. Histopathology of the lung was examined and the expression of CSE and TNF-α mRNA in lung tissue was detected by real-time polymerase chain reaction. The H2S level in the serum was detected spectrophotometrically.ResultsThe serum concentration of H2S and CSE and TNF-α expression in the lung were increased in AP rats modeled after 3 h and 6 h than in control rats (p < 0.05). Intraperitoneal injection of PAG could reduce the serum concentration of H2S, reduce CSE and TNF-α expression, and alleviate the lung pathology (p < 0.05).ConclusionsTaken together, our findings suggest that the H2S/CSE system is crucially involved in the pathological process of APALI and represents a novel target for the therapy of APALI.

Early Activation of Pulmonary TGF-β1/Smad2 Signaling in Mice with Acute Pancreatitis-Associated Acute Lung Injury

Acute lung injury is caused by many factors including acute pancreatitis. There is no specific therapy directed at underlying pathophysiological mechanisms for acute lung injury. Transforming growth factor-β (TGF-β) is involved in the resolution of lung injury in later phases of the disease. Some evidence exists demonstrating that TGF-β not only is involved in the late stages, but also contributes to lung injury early on in the progress of the disease. Acute pancreatitis was induced using ductal ligation in mice. TGF-β1, 2, and 3, TβRII, ALK-5, Smad2, 3, 4, and 7, and P-Smad2 expression in the lungs were analyzed at 9 and 24 h. We demonstrate that TGF-β1 levels in the lungs of mice with acute pancreatitis increase as early as 9 h after induction. We observed an increased expression of ALK-5 in acute pancreatitis at both 9 and 24 h. Inhibitory Smad7 expression was transiently increased at 9 h in acute pancreatitis, but reduced later at 24 h, with a concomitant increased nuclear translocation of phosphorylated Smad2. Our findings demonstrate activation of TGF-β signaling in the lungs as early as 24 h after acute pancreatitis, suggesting that TGF-β may represent a potential therapeutic candidate in acute pancreatitis-induced acute lung injury.