|Year : 2016 | Volume
| Issue : 14 | Page : 1719-1724
Inhibition of c-Jun N-terminal Kinase Signaling Pathway Alleviates Lipopolysaccharide-induced Acute Respiratory Distress Syndrome in Rats
Jian-Bo Lai, Chun-Fang Qiu, Chuan-Xi Chen, Min-Ying Chen, Juan Chen, Xiang-Dong Guan, Bin Ouyang
Department of Critical Care Medicine, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
|Date of Submission||29-Feb-2016|
|Date of Web Publication||11-Jul-2016|
Dr. Bin Ouyang
Department of Critical Care Medicine, First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan Er Lu, Guangzhou, Guangdong 510080
Source of Support: None, Conflict of Interest: None
Background: An acute respiratory distress syndrome (ARDS) is still one of the major challenges in critically ill patients. This study aimed to investigate the effect of inhibiting c-Jun N-terminal kinase (JNK) on ARDS in a lipopolysaccharide (LPS)-induced ARDS rat model.
Methods: Thirty-six rats were randomized into three groups: control, LPS, and LPS + JNK inhibitor. Rats were sacrificed 8 h after LPS treatment. The lung edema was observed by measuring the wet-to-dry weight (W/D) ratio of the lung. The severity of pulmonary inflammation was observed by measuring myeloperoxidase (MPO) activity of lung tissue. Moreover, the neutrophils in bronchoalveolar lavage fluid (BALF) were counted to observe the airway inflammation. In addition, lung collagen accumulation was quantified by Sircol Collagen Assay. At the same time, the pulmonary histologic examination was performed, and lung injury score was achieved in all three groups.
Results: MPO activity in lung tissue was found increased in rats treated with LPS comparing with that in control (1.26 ± 0.15 U in LPS vs. 0.77 ± 0.27 U in control, P < 0.05). Inhibiting JNK attenuated LPS-induced MPO activity upregulation (0.52 ± 0.12 U in LPS + JNK inhibitor vs. 1.26 ± 0.15 U in LPS, P < 0.05). Neutrophils in BALF were also found to be increased with LPS treatment, and inhibiting JNK attenuated LPS-induced neutrophils increase in BALF (255.0 ± 164.4 in LPS vs. 53 (44.5-103) in control vs. 127.0 ± 44.3 in LPS + JNK inhibitor, P < 0.05). At the same time, the lung injury score showed a reduction in LPS + JNK inhibitor group comparing with that in LPS group (13.42 ± 4.82 vs. 7.00 ± 1.83, P = 0.001). However, the lung W/D ratio and the collagen in BALF did not show any differences between LPS and LPS + JNK inhibitor group.
Conclusions: Inhibiting JNK alleviated LPS-induced acute lung inflammation and had no effects on pulmonary edema and fibrosis. JNK inhibitor might be a potential therapeutic medication in ARDS, in the context of reducing lung inflammatory.
Keywords: Acute Respiratory Distress Syndrome; c-Jun N-terminal Kinase Inhibitor; Lung Inflammation C14H8N2O
|How to cite this article:|
Lai JB, Qiu CF, Chen CX, Chen MY, Chen J, Guan XD, Ouyang B. Inhibition of c-Jun N-terminal Kinase Signaling Pathway Alleviates Lipopolysaccharide-induced Acute Respiratory Distress Syndrome in Rats. Chin Med J 2016;129:1719-24
|How to cite this URL:|
Lai JB, Qiu CF, Chen CX, Chen MY, Chen J, Guan XD, Ouyang B. Inhibition of c-Jun N-terminal Kinase Signaling Pathway Alleviates Lipopolysaccharide-induced Acute Respiratory Distress Syndrome in Rats. Chin Med J [serial online] 2016 [cited 2018 Aug 17];129:1719-24. Available from: http://www.cmj.org/text.asp?2016/129/14/1719/185867
| Introduction|| |
The incidence of acute respiratory distress syndrome (ARDS) has reached up to 5.0–33.8/100,000 population per year according to the recent epidemiological studies.,,, The overall mortality of ARDS remains at 40–50%. Therefore, it is still a big challenge for both critically ill patients and clinicians.,, New strategies are required urgently in ARDS management.
The uncontrolled inflammatory cascade has been considered to be the main cause of the ARDS and leads to multiple organ dysfunction syndrome.,, Earlier studies have tried to block some of the inflammatory mediators but failed to generate a significant therapeutic effect in ARDS.,,, During the last decade, the inflammatory cascade was found to be activated through a rapid responding intracellular signaling system in the plasma. c-Jun N-terminal kinase (JNK) was first found to be one of the intracellular signaling pathways related with stress and inflammation; therefore, it was originally named as a stress-activated protein kinase. Now, JNK was known to be a member of mitogen-activated protein kinase (MAPK) family responsible for the cytokine production in the stress progress. Recently, studies confirmed that blocking JNK with a selectively JNK inhibitor SP600125 was a promising therapeutic strategy in inhibiting inflammatory process in brain injury, senile dementia, and Parkinson's disease.
Inhibiting JNK might also be beneficial in acute lung injury.,, We therefore examined whether JNK inhibition could act as a new therapeutic strategy in preventing ARDS progression, particularly in pulmonary inflammation, edema, and fibrosis.
| Methods|| |
Thirty-six male Sprague-Dawley rats aged 7–8 weeks (180–280 g) were purchased from the Medical Experimental Center of Southern Medical University, Guangzhou, China (License No.: SCXK[Guangdong]-2011-0015). The experimental protocol was approved by the Animal Care Committee of the Ethical Committee on Animal Research at Sun Yat-Sen University. All procedures were performed strictly according to the National Institute of Health Guide for the Care and Use of Laboratory Animals.
SP600125, the JNK inhibitor (C14H8N2O, powder, 50 mg/bottle) was purchased from the Biomol Co., (Exeter, UK). Lipopolysaccharide (LPS) was purchased from Escherichia More Details coli (Sigma-Aldrich, St. Louis, USA). Masson trichrome staining solution was purchased from Sigma Chemical Co., (St. Louis, USA). The myeloperoxidase (MPO) determination kit was purchased from Nanjing Jiancheng Bioengineering Institute (Jiangsu, China). The mouse radioimmunoassay kit was purchased from Radioimmunoassay Institute of the General Hospital of Chinese People's Liberation Army (Beijing, China). Soluble collagen kit was purchased from Biocolor Ltd., (Antrim, UK).
Thirty-six rats were divided randomly into three groups: control, LPS, and LPS + JNK inhibitor (SP600125). All rats were anesthetized with 10% chloral hydrate (300 mg/kg body weight) before any procedures. Sodium chloride (0.9%, 0.5 ml) was given intratracheally in the control group. LPS (10 mg/kg, 0.5 ml) was given intratracheally in the LPS group. JNK inhibitor (SP600125, 10 mg/kg) was administered intravenously through caudal vein following LPS injection (10 mg/kg, 0.5 ml) intratracheally in the LPS + JNK inhibitor group. Moreover, an equal volume of the solvent of SP600125 (glycol, 20% polypropylene glycol, 15% polyoxyethylated castor oil, 5% ethanol, and 30% normal saline) was injected intravenously in both control group and LPS group.
Bronchoalveolar lavage and lung tissue harvesting
All rats were sacrificed at 8 h after LPS administration. The bronchoalveolar lavage was performed with intratracheal instillation of 6 ml normal saline into the right lower lobe. BALF was collected for neutrophils counting. The right upper lobe was also used for Masson trichrome collagen staining. The right middle lobe was used to determine MPO activity. The left lower lobe was harvested for the measurement of wet-to-dry weight (W/D) ratio of the lung. The left upper lobe was fixed with 5% formaldehyde for hematoxylin and eosin (H and E) staining.
Pathologic observation of lung tissue
The lung sections were fixed in 5% formaldehyde solution and stained with H and E. Pathological changes of lung tissue were evaluated under a light microscope (Olympus BX51, Tokyo, Japan). A previously described scoring system was used for quantification of lung injury severity. The pathological features were determined by the following changes: focal thickening of alveolar membrane, capillary congestion, intra-alveolar hemorrhage, pulmonary interstitial neutrophil infiltration, and intra-alveolar neutrophil infiltration. Each feature was scored from 0 to 3 based on absence (0), presence or mild (1), moderate (2), and severe (3). A total histology score (THS) was then calculated.
Neutrophils count in the bronchoalveolar lavage fluid
The neutrophils in bronchoalveolar lavage fluid (BALF) were counted under a light microscope (Olympus BX51, Tokyo, Japan).
Myeloperoxidase activity of the lung tissue
Lung tissue (100 mg) was homogenized in 2 ml extraction buffer. MPO activity was then measured according to the instruction provided by the manufacturer (Nanjing Jiancheng Bioengineering Institute, Jiangsu, China). The optical density of the microplates was read at 460 nm in a plate reader (Thermo Multiskan MK3, Philadelphia, PA, USA).
Lung wet-to-dry weight ratio
The wet weight of lung tissue was measured once the lung was harvested. The dry weight was obtained by placing the lung tissue into an 80°C incubator (LW Scientific Incubator-30L/1 Cubic ft, Lawrenceville, GA, USA) for 48–72 h till the weight getting stable.
Collagen measurement in lung tissue
The lung tissue was homogenized in 1 ml of Sircol reagent for 30 min and then centrifuged at 5000 ×g for 10 min. The pellet was then transferred into 1 ml of soda reagent. Collagen was measured with Sircol ™ Collagen Assay kit according to the manufacturer's instruction (Biocolor Ltd., Carrickfergus, County Antrim, UK).
Masson's trichrome staining of the collagen in lung tissue
The lung sections were fixed in 5% formaldehyde solution and stained with Masson trichrome staining solution according to the instruction provided by the manufacturer (Sigma Chemical Co., St. Louis, USA). Collagen deposition was evaluated under a light microscope (Olympus BX51, Tokyo, Japan).
The SPSS 13.0 software (SPSS Inc., Chicago, IL, USA) was used for the data analysis. The normal distribution of quantitative data is tested by Kolmogorov-Smirnov and Shapiro-Wilk tests. The quantitative data were expressed as a mean ± standard deviation (SD) for normal distribution and median (interquartile range) for non-normal distribution. These data were analyzed using one-way analysis of variance (ANOVA) followed by a Tukey's post hoc test for normal distribution data and Dunnet's post hoc test for non-normal distribution data. A value of P < 0.05 was considered to denote a significant difference for all analyses.
| Results|| |
Pathological observation of lung tissue
The structure of the alveoli in the control group was complete and there was no obvious pathological change under a light microscope [Figure 1]a. The structure of alveoli in LPS group was destroyed and the inflammatory cells, mainly neutrophils, were found widely spread in most alveoli. Red blood cells and fibrin were exuded into alveoli and spread along alveolar-capillary membrane [Figure 1]b. In LPS + JNK inhibitor group, the structure of the alveoli was partially restored compared with that in LPS group. The neutrophils and red blood cells infiltration were reduced comparing with that in LPS group. The alveolar-capillary interval was not as thick as that in LPS group [Figure 1]c.
|Figure 1: Effects of the JNK inhibitor on lung injury in LPS-treated rats. Representative lung specimens obtained from the control group (a: Control group; b: LPS group,and c: LPS + JNK inhibitor group, original magnification ×100, Hematoxylin and Eosin Staining). The neutrophil counts in large and small airways, and hemorrhage markedly decreased on JNK inhibitor treated group. The red arrow points to the neutrophils and red blood cells infiltration. JNK: c-Jun N-terminal kinase; LPS: Lipopolysaccharide.|
Click here to view
THS of lung injury was significantly higher in the LPS group comparing with that in control group (13.42 ± 4.82 vs. 3.60 ± 0.55, P = 0.001). Meanwhile, THS decreased significantly in the LPS + JNK inhibitor group comparing with that in LPS group (7.00 ± 1.83, P = 0.001) [Figure 2].
|Figure 2: The total histology score was significantly lower in the LPS + JNK inhibitor group than that in the LPS group. The values presented are the mean ± SD (n = 12 in each group). *P < 0.05 versus control. †P < 0.05 versus LPS group. JNK: c-Jun N-terminal kinase; LPS: Lipopolysaccharide; SD: Standard deviation.|
Click here to view
Neutrophils in bronchoalveolar lavage fluid
The neutrophils in BALF increased significantly in LPS group compared with that in control group (255 ± 164.4/ml vs. 53 (58.5) ml, P < 0.05). It was significantly reduced in LPS + JNK inhibitor group comparing with that in LPS group (255.0 ± 164.4/ml vs. 127.0 ± 44.3/ml, P < 0.05) [Figure 3].
|Figure 3: The amount of neutrophils in BALF was significantly lower in the LPS + JNK inhibitor group than that in the LPS group. The values presented are the mean ± SD (n = 12 in each group). *P < 0.05 versus control. †P < 0.05 versus LPS group. BALF: Bronchoalveolar lavage fluid; LPS: Lipopolysaccharide; JNK: c-Jun N-terminal kinase; SD: Standard deviation.|
Click here to view
Myeloperoxidase activity in the lung tissue
MPO activity in the lung tissue increased significantly in the rats treated with LPS comparing with that in control group (1.26 ± 0.15 U/mg in LPS group vs. 0.77 ± 0.27 U/mg in control group, P < 0.05). Moreover, this increase was reduced significantly in rats treated with SP600125 (1.26 ± 0.15 U/mg in LPS group vs. 0.52 ± 0.12 U/mg in LPS + JNK inhibitor group, P < 0.05) [Figure 4].
|Figure 4: MPO activity. Higher MPO activity was induced after LPS injection, and MPO activity was significantly lower in animals in the LPS + JNK inhibitor group than that in the LPS group. The values presented are the mean ± SD (n = 12 in each group). *P < 0.05 versus control. †P < 0.05 versus LPS group. MPO: Myeloperoxidase; LPS: Lipopolysaccharide; JNK: c-Jun N-terminal kinase; SD: Standard deviation.|
Click here to view
Wet-to-dry weight ratio of lung tissue
No significant difference was found in W/D ratios of lung tissues among three groups (0.20 ± 0.02 in control group vs. 0.18 ± 0.02 in LPS group vs. 0.18 ± 0.02 in LPS + JNK inhibitor group, P > 0.05) [Figure 5].
|Figure 5: W/D ratio of lung tissue. No significant difference was found in W/D ratio of the lung tissue among the three groups. The values presented are the mean ± SD (n = 12 in each group). SD: Standard deviation; W/D: Wet-to-dry weight.|
Click here to view
Collagen content in lung tissue
Collagen content in lung tissue was significantly higher in LPS group than that in control group (45.08 ± 5.97 mg/g in LPS group vs. 8.65 ± 6.74 mg/g in control group, P < 0.05). However, there was no significant difference between LPS + JNK inhibitor group and LPS group (52.08 ± 14.06 mg/g in LPS + JNK inhibitor vs. 45.08 ± 5.97 mg/g in LPS group, P > 0.05) [Figure 6].
|Figure 6: Collagen content in lung tissue. Collagen content in lung tissue was significantly higher in LPS group than that in control group. There was no significant change between LPS group and LPS + JNK inhibitor group. The values presented are the mean ± SD (n = 12 in each group). *P < 0.05 versus control. LPS: Lipopolysaccharide; JNK: c-Jun N-terminal kinase; SD: Standard deviation.|
Click here to view
Masson's trichrome staining of the collagen in lung tissue
No collagen deposition was observed in control group [Figure 7]a. Slight collagen deposition was found in both LPS group and LPS + JNK inhibitor group but no obvious difference was found between these two groups [Figure 7]b and [Figure 7]c.
|Figure 7: Masson's trichrome staining of the collagen in lung tissue specimens after LPS administration in rats. Representative lung specimens obtained from the control group (a: original magnification ×200), LPS group (b: original magnification ×200), and LPS + JNK inhibitor group (c: original magnification ×200). Collagen deposition was obvious in lung tissue in LPS and JNK inhibitor group. There was no significant difference between LPS + JNK inhibitor group and LPS group. The red arrow points to collagen deposition. LPS: Lipopolysaccharide; JNK: c-Jun N-terminal kinase.|
Click here to view
| Discussion|| |
In this study, we investigated the effect of a JNK selective inhibitor, SP600125, in a rat model of LPS-induced ARDS. Pulmonary inflammation, fibrosis, and edema were all studied to evaluate the effects of inhibiting JNK pathway on ARDS. Acute lung inflammation was one of the major pathological changes occurring in ARDS. In this study, we found that JNK inhibitor administration resulted in a significant attenuation of LPS-induced acute pulmonary inflammation. The alveoli structure was partially restored, the neutrophils infiltration was reduced, and the alveolar-capillary interval was normal in rats treated with JNK inhibitor. These findings were consisted with Lee et al. and Arndt et al.'s  study in ARDS model, which showed JNK inhibition alleviated LPS-induced neutrophils infiltration in the lung. However, the studies by Lee et al. and Arndt et al. were only focused on inflammation but not lung fibrosis and edema. Lung collagen accumulation and edema were found existed early in ARDS and associated with poor prognosis of ARDS patients.,, In this study, we demonstrated that JNK inhibitor alleviated lung inflammation but had no effect on lung collagen accumulation and lung edema. This implicated the efficacy of JNK inhibitor in inflammation and also the safety in edema and fibrosis as a possible therapeutic drug in ARDS in the future.
Lung collagen accumulation was caused by increased synthesis of procollagen I and/or imbalanced synthesis and degradation of collagen in the early stage of ARDS., A previous study by our colleagues showed that transforming growth factor-β (TGF-β) was a critical cytokine that regulated the synthesis of procollagen I and homeostasis of collagen. TGF-β1 was found to work through the p38 MAPK signal pathway but not JNK.,,,,,,, Thus, we postulated that p38, but not JNK, was involved in the LPS-induced acute pulmonary fibroproliferation and JNK inhibitor had no obvious effect on pulmonary fibrosis in ARDS.
Pulmonary edema is another main pathological change of ARDS, which occurred due to impaired alveolar fluid clearance, increased capillary endothelial permeability, and damaged alveolar epithelial barrier. In a recent study by Zheng et al., the lung edema was significantly attenuated with JNK inhibitor. However, in this study, no significant difference was found among control, LPS group, and LPS + JNK inhibitor group. Other pathways might be involved in LPS-induced lung edema. In our previous study, we found that LPS-induced dysfunction of airway epithelial barrier in ARDS and p38 was involved in the LPS-induced dysfunction of airway epithelial barrier. An earlier study by Migneault et al. also reported that LPS downregulates ENaC mRNA via ERK1/2 and p38 MAPK in alveolar epithelial cells. Frank et al.found that TGF-β1 downregulated the expression of ENaC, an important sodium channel in the surface of alveolar epithelial cells, and affected the liquid transport in the alveoli. Whether the crosstalk existed between JNK and these factors needs more investigation.
The present study had some limitations. SP600125 is a general inhibitor of JNK family including JNK1, JNK2, and JNK3. Further research might be needed to investigate the detail underlying mechanism of JNK family.
In conclusion, our results indicated that inhibition of JNK exerted its anti-inflammatory activity without any effects on pulmonary fibrosis and edema in ARDS. Taking together, manipulation of JNK/MAPK pathway could be a potential therapeutic target for ARDS in the context of suppressing inflammation.
Financial support and sponsorship
This work was supported by the Science and Technology Project in Guangdong, China (No. 2010B 031600314).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Linko R, Okkonen M, Pettilä V, Perttilä J, Parviainen I, Ruokonen E, et al.
Acute respiratory failure in intensive care units. FINNALI: A prospective cohort study. Intensive Care Med 2009;35:1352-61. doi: 10.1007/s00134-009-1519-z.
Li G, Malinchoc M, Cartin-Ceba R, Venkata CV, Kor DJ, Peters SG, et al.
Eight-year trend of acute respiratory distress syndrome: A population-based study in Olmsted County, Minnesota. Am J Respir Crit Care Med 2011;183:59-66. doi: 10.1164/rccm.201003-0436OC.
Villar J, Blanco J, Añón JM, Santos-Bouza A, Blanch L, Ambrós A, et al.
The ALIEN study: Incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med 2011;37:1932-41. doi: 10.1007/s00134-011-2380-4.
Sigurdsson MI, Sigvaldason K, Gunnarsson TS, Moller A, Sigurdsson GH. Acute respiratory distress syndrome: Nationwide changes in incidence, treatment and mortality over 23 years. Acta Anaesthesiol Scand 2013;57:37-45. doi: 10.1111/aas.12001.
Phua J, Badia JR, Adhikari NK, Friedrich JO, Fowler RA, Singh JM, et al.
Has mortality from acute respiratory distress syndrome decreased over time?: A systematic review. Am J Respir Crit Care Med 2009;179:220-7. doi: 10.1164/rccm.200805-722OC.
Petrucci N, De Feo C. Lung protective ventilation strategy for the acute respiratory distress syndrome. Cochrane Database Syst Rev 2013;2:CD003844. doi: 10.1002/14651858.CD003844.pub4.
National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, et al.
Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354:2564-75. doi: 10.1056/NEJMoa062200.
Galani V, Tatsaki E, Bai M, Kitsoulis P, Lekka M, Nakos G, et al.
The role of apoptosis in the pathophysiology of Acute Respiratory Distress Syndrome (ARDS): An up-to-date cell-specific review. Pathol Res Pract 2010;206:145-50. doi: 10.1016/j.prp.2009.12.002.
Meduri GU, Annane D, Chrousos GP, Marik PE, Sinclair SE. Activation and regulation of systemic inflammation in ARDS: Rationale for prolonged glucocorticoid therapy. Chest 2009;136:1631-43. doi: 10.1378/chest.08-2408.
Fujishima S, Morisaki H, Ishizaka A, Kotake Y, Miyaki M, Yoh K, et al.
Neutrophil elastase and systemic inflammatory response syndrome in the initiation and development of acute lung injury among critically ill patients. Biomed Pharmacother 2008;62:333-8. doi: 10.1016/j.biopha.2007.07.003.
Wu CL, Lin LY, Yang JS, Chan MC, Hsueh CM. Attenuation of lipopolysaccharide-induced acute lung injury by treatment with IL-10. Respirology 2009;14:511-21. doi: 10.1111/j.1440-1843.2009.01516.x.
Tajima S, Soda M, Bando M, Enomoto M, Yamasawa H, Ohno S, et al.
Preventive effects of edaravone, a free radical scavenger, on lipopolysaccharide-induced lung injury in mice. Respirology 2008;13:646-53. doi: 10.1111/j.1440-1843.2008.01322.x.
Hou YC, Pai MH, Chiu WC, Hu YM, Yeh SL. Effects of dietary glutamine supplementation on lung injury induced by lipopolysaccharide administration. Am J Physiol Lung Cell Mol Physiol 2009;296:L288-95. doi: 10.1152/ajplung.90479.2008.
Chen Z, Zhang X, Chu X, Zhang X, Song K, Jiang Y, et al.
Preventive effects of valnemulin on lipopolysaccharide-induced acute lung injury in mice. Inflammation 2010;33:306-14. doi: 10.1007/s10753-010-9186-3.
Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, et al.
Mitogen-activated protein (MAP) kinase pathways: Regulation and physiological functions. Endocr Rev 2001;22:153-83. doi: 10.1210/edrv.22.2.0428.
Wolf PS, Merry HE, Farivar AS, McCourtie AS, Mulligan MS. Stress-activated protein kinase inhibition to ameliorate lung ischemia reperfusion injury. J Thorac Cardiovasc Surg 2008;135:656-65. doi: 10.1016/j.jtcvs.2007.11.026.
Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 2010;1802:396-405. doi: 10.1016/j.bbadis.2009.12.009.
Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, Xu W, et al.
SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A 2001;98:13681-6. doi: 10.1073/pnas.251194298.
Lee HS, Kim HJ, Moon CS, Chong YH, Kang JL. Inhibition of c-Jun NH2-terminal kinase or extracellular signal-regulated kinase improves lung injury. Respir Res 2004;5:23. doi: 10.1186/1465-9921-5-23.
Murao Y, Loomis W, Wolf P, Hoyt DB, Junger WG. Effect of dose of hypertonic saline on its potential to prevent lung tissue damage in a mouse model of hemorrhagic shock. Shock 2003;20:29-34. doi: 10.1097/01.shk.0000071060.78689.f1.
Arndt PG, Young SK, Lieber JG, Fessler MB, Nick JA, Worthen GS. Inhibition of c-Jun N-terminal kinase limits lipopolysaccharide-induced pulmonary neutrophil influx. Am J Respir Crit Care Med 2005;171:978-86. doi: 10.1164/rccm.200406-712OC.
Santos FB, Nagato LK, Boechem NM, Negri EM, Guimarães A, Capelozzi VL, et al.
Time course of lung parenchyma remodeling in pulmonary and extrapulmonary acute lung injury. J Appl Physiol (1985) 2006;100:98-106. doi: 10.1152/japplphysiol.00395.2005.
Rocco PR, Souza AB, Faffe DS, Pássaro CP, Santos FB, Negri EM, et al.
Effect of corticosteroid on lung parenchyma remodeling at an early phase of acute lung injury. Am J Respir Crit Care Med 2003;168:677-84. doi: 10.1164/rccm.200302-256OC.
Marshall RP, Bellingan G, Webb S, Puddicombe A, Goldsack N, McAnulty RJ, et al.
Fibroproliferation occurs early in the acute respiratory distress syndrome and impacts on outcome. Am J Respir Crit Care Med 2000;162:1783-8. doi: 10.1164/ajrccm.162.5.2001061.
Budinger GR, Chandel NS, Donnelly HK, Eisenbart J, Oberoi M, Jain M. Active transforming growth factor-beta1 activates the procollagen I promoter in patients with acute lung injury. Intensive Care Med 2005;31:121-8. doi: 10.1007/s00134-004-2503-2.
Dhainaut JF, Charpentier J, Chiche JD. Transforming growth factor-beta: A mediator of cell regulation in acute respiratory distress syndrome. Crit Care Med 2003;31 4 Suppl:S258-64. doi: 10.1097/01.CCM.0000057901.92381.75.
Fahy RJ, Lichtenberger F, McKeegan CB, Nuovo GJ, Marsh CB, Wewers MD. The acute respiratory distress syndrome: A role for transforming growth factor-beta 1. Am J Respir Cell Mol Biol 2003;28:499-503. doi: 10.1165/rcmb.2002-0092OC.
Liu S, Feng G, Wang GL, Liu GJ. p38MAPK inhibition attenuates LPS-induced acute lung injury involvement of NF-kappaB pathway. Eur J Pharmacol 2008;584:159-65. doi: 10.1016/j.ejphar.2008.02.009.
Painemal P, Acuña MJ, Riquelme C, Brandan E, Cabello-Verrugio C. Transforming growth factor type beta 1 increases the expression of angiotensin II receptor type 2 by a SMAD- and p38 MAPK-dependent mechanism in skeletal muscle. Biofactors 2013;39:467-75. doi: 10.1002/biof.1087.
Ferrari G, Terushkin V, Wolff MJ, Zhang X, Valacca C, Poggio P, et al.
TGF-ß1 induces endothelial cell apoptosis by shifting VEGF activation of p38(MAPK) from the prosurvival p38ß to proapoptotic p38a. Mol Cancer Res 2012;10:605-14. doi: 10.1158/1541-7786.MCR-11-0507.
Pejchal J, Novotný J, Marák V, Osterreicher J, Tichý A, Vávrová J, et al.
Activation of p38 MAPK and expression of TGF-ß1 in rat colon enterocytes after whole body γ-
irradiation. Int J Radiat Biol 2012;88:348-58. doi: 10.3109/09553002.2012.654044.
Kolosova I, Nethery D, Kern JA. Role of Smad2/3 and p38 MAP kinase in TGF-ß1-induced epithelial-mesenchymal transition of pulmonary epithelial cells. J Cell Physiol 2011;226:1248-54. doi: 10.1002/jcp.22448.
Redondo S, Ruiz E, Gordillo-Moscoso A, Navarro-Dorado J, Ramajo M, Carnero M, et al.
Role of TGF-beta1 and MAP kinases in the antiproliferative effect of aspirin in human vascular smooth muscle cells. PLoS One 2010;5:e9800. doi: 10.1371/journal.pone.0009800.
Tong XK, Hamel E. Transforming growth factor-beta 1 impairs endothelin-1-mediated contraction of brain vessels by inducing mitogen-activated protein (MAP) kinase phosphatase-1 and inhibiting p38 MAP kinase. Mol Pharmacol 2007;72:1476-83. doi: 10.1124/mol.107.039602.
Kim SI, Kwak JH, Zachariah M, He Y, Wang L, Choi ME. TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen. Am J Physiol Renal Physiol 2007;292:F1471-8. doi: 10.1152/ajprenal.00485.2006.
Frank J, Roux J, Kawakatsu H, Su G, Dagenais A, Berthiaume Y, et al.
Transforming growth factor-beta1 decreases expression of the epithelial sodium channel alphaENaC and alveolar epithelial vectorial sodium and fluid transport via an ERK1/2-dependent mechanism. J Biol Chem 2003;278:43939-50. doi: 10.1074/jbc.M304882200.
Zheng Y, Zhang M, Zhao Y, Chen J, Li B, Cai W. JNK inhibitor SP600125 protects against lipopolysaccharide-induced acute lung injury via upregulation of claudin-4. Exp Ther Med 2014;8:153-8. doi: 10.3892/etm.2014.1684.
Ma J, Ouyang B, Lai JB, Guan XD. Engagement of p38 mitogen-activated protein kinase in regulation of epithelial barrier of acute respiratory distress syndrome (in Chinese). Chin Crit Care Med 2013;25:589-93. doi: 10.3760/cma.j.issn.2095-4352.2013.10.004.
Migneault F, Boncoeur E, Morneau F, Pascariu M, Dagenais A, Berthiaume Y. Cycloheximide and lipopolysaccharide downregulate aENaC mRNA via different mechanisms in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 2013;305:L747-55. doi: 10.1152/ajplung.00023.2013.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]