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��ࡱ�>��	8:����567�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������'`	��Fbjbj���	;V����%�=_�����������LLL�$|u|u|u8�u$�w\�&��F@x�.y@nyny�y|||��������������$�hv�����Lň||ňň����ny�y|��1�1�1�ň��	nyL�y��1�ň��1�1��_�h��LS�ny,4x�	�����|uӐ&ǟS�D��0��ן|J���"J� S�a�bJ�Lû�|@ZR1������=|||�����|||��ňňňň�&�P6��EDdd�&P6�Ed`d�������������Heparin inhibits burn-induced spleen apoptosis by suppressing IL-1 expression 
     Zhao, Songfeng M.D, Ph.D; Zhang, Xiao M.D; Zhang, Xiaojian M.D; Shi, Xiuqin M.D; Yu, Zujiang M.D, Ph.D; Kan, Quancheng M.D, Ph.D
Department of pharmacology, The First Affiliated Hospital, Zhengzhou University, No.1 Jianshe Road, Zhengzhou, Henan, 450052 China; The Provincial Key Lab of Clinical Medicine, The First Affiliated Hospital, Zhengzhou University, No.1 Jianshe Road, Zhengzhou, Henan, 450052 China
Address correspondence to:
Quancheng Kan, MD, PhD
Department of pharmacology, 
The First Affiliated Hospital, 
Zhengzhou University, 
No. 1 Jianshe Road,
Zhengzhou, Henan, 450052, China
Phone: 86- 371-66989940
Fax: 86- 371-66989941
E-mail:  HYPERLINK "mailto:johyu@zzu.edu.cn" johyu@zzu.edu.cn
Acknowledgements: 
      This work was supported by the China National Nature Science Grant: No. 30472031 to Dr. Quancheng Kan. We thank Dr. Michelle Markle from Harvard University for grammar and spelling checking in this paper.
Disclosure:
      The authors declare that no conflict of interest exists


ABSTRACT
Objective: Epidermal burn injury may induce significant spleen apoptosis. Heparin has been shown to possess anti-inflammatory properties. We hypothesized heparin might inhibit burn-induced spleen apoptosis via its anti-inflammatory activity. 
Methods: Burn injury was performed on IL-1 R +/+ and IL-1 R -/- mice, and then treated with heparin. Apoptosis, and IL-1� and IL-1� expression were assessed in spleens. Survival curve analysis and IL-1 receptor antagonist (IL-1Ra) were further applied to elucidate the mechanism under heparin s protective property. 
Results: Burn significantly induced apoptosis (Sham: 3.6 �2.1% v.s burn: 28.8� 5.9%; P< 0.001) and remarkable expression of both IL-1� and IL-1� in mouse spleen. Heparin reduced the burn-induced spleen apoptosis (Heparin treated: 8.6 �3.4%, P<0.005), which could be blocked by IL-1Ra. Heparin markedly decreased both IL-1� and IL-1� expressions in the spleens of burned mice. IL-1 R -/- mice demonstrated considerably less apoptosis in spleens and higher survival rate after burn. Heparin did not significantly decrease apoptosis in spleen and mortality rate in IL-1 R -/- mice after burn.  
Conclusions:  Heparin inhibits burn-induced spleen apoptosis by suppressing IL-1 expression in mice. 






Key words: burn; spleen; apoptosis; heparin; IL-1
Introduction
      Burn injury occurs frequently, claiming thousands of lives and causing significant physical and psychological disabilities throughout the world. Clinically, burn patients are at a greater risk of systemic and topical infections. 1, 2 As the thymus degenerates with age, the spleen plays a pivotal role in human immune defenses. It is not known whether severe burn trauma causes spleen dysfunction which might contribute to patients vulnerability to infections. 3 Burn injury may induce cellular apoptosis in the spleen which might relate to the potentiality of spleen dysfunction in burned patients. 4 
      Low Molecular Weight (LMW) heparin is a glycosaminoglycan which is clinically administrated as a strong antithrombotic agent. Evidence demonstrates heparin reduces the local and systemic inflammatory response through unknown mechanisms. 5 Data also suggests that heparin blocks the activities of some important proinflammatory cytokines, 6, 7 and these cytokines are found to be involved highly in cellular apoptosis. 8 However, it is not well understood whether heparin decreases cellular apoptosis. 
Interleukin 1 (IL-1) is a central cytokine which plays an important role in immune reaction and inflammation. It has been shown that IL-1 promotes leukocyte recruitment and might initiate cellular apoptosis as a potent extracellular stimulator. 9 Carlos Ramos found that heparin reduced IL-1 expression and apoptosis in normal human lung fibroblasts. 10   Burn injury can induce significant inflammatory reactions in remote organs, including the spleen. The local or systemic inflammatory response might trigger or promote cellular apoptosis. 11 To date, it has not been documented whether heparin suppresses the susceptibility to apoptosis in the spleen through its anti-inflammatory properties. We hypothesized that burn injury might introduce cellular apoptosis in the spleen, while heparin reduces this apoptosis by decreasing the cytokines, such as IL-1. To test this hypothesis, an experimental thermal injury model was introduced in mice and then these mice were treated with heparin (as described below). 
Methods 
Materials
      Ketamine, Xylazine and IL-1 receptor inhibitor (recombined IL-1R�) were from Sigma-Aldrich (Cambridge, MA, U.S.A). Cleaved anti-IL-1 alpha antibody, cleaved anti-IL-1 beta, HRP-linked anti-rabbit IgG, HRP-linked anti-mouse IgG and anti-GAPDH antibody were from Cell Signaling (Danvers, MA, U.S.A). In Situ Apoptosis Detection kit was obtained from millipore (Temecula, CA, U.S.A). Polyvinylidene difluoride membranes were obtained from Amersham Biosciences (Buckinghamshire, UK). Heparin Sodium Salt was bought from MP Biomedicals, LLC. O.H. Mouse IL-1 alpha and IL-beta ELISA kits were from Abcam, Cambridge, MA.   
Animals
     An eight-week old inbred male IL-1R knock-out mice (IL-1R -/-, Genotype: IL-1 tm1Hbg /J) and a wild-type control mice (IL-1R +/+, C57BL/6J), weighing 22-26g, were obtained from the Shanghai MAOSHENG Biologic Science & Technology Development Co. Ltd, a Sub-distributor of U.S.A Jackson Laboratory. All the procedures were done in accordance with the protocol approved by the committee on research animal care at Zhengzhou University, and complied with the Eighth Edition of the Guide for the Care and Use of Laboratory Animals (NRC 2011). 
Skin burn injury in mice
      Only male mice were used in the present study. General anesthesia was performed (Ketamine 40mg/kg and Xylazine 5 mg/kg body weight, I.P) prior to the burn injury.  A full-thickness thermal injury of 30% total body surface area (TBSA) on the back was produced by exposing the shaved dorsal skin to a 90 oC water bath for 12 seconds. According to the Parkland formula guidelines for the liquid resuscitation for the mice, the mice received 2.0 mL of saline by intraperitoneal injection immediately after the burn injury. Sham control mice were treated using a room-temperature water bath. Immediately following the burn injury, the heparin-treated mice were injected with 20mg/kg of heparin subcutaneously, and a second and third dose was administered 8 and 16 hours later, respectively. The antagonist-treated mice were administered 50(g/kg of IL-1 receptor antagonist (IL-1Ra) immediately after the injury via tail vein injection and a second dose was administered 12 hours through the same methods. In the control group, sham treated mice received the same volumes of saline at the same dosing time.
Body surface area (BSA) was calculated based on the formula: BSA = K � W2/3, where W = body weight in grams and K is a shape constant for a given species. 12 Thus the following formulae was used for calculating mouse BSA: mouse, 20 � W0.42. 
We used much higher dose of heparin for the treatment which might result in bleeding complication. We performed dose response studies in conjunction with activated partial thromboplastin time (APTT) test. We found the current dose of 20mg/kg prolonged ATPP from normal 30�2.8 seconds to 320�36 seconds, but caused no significant bleeding complication or related death. 
Survival Analysis
In our study, the mortality of these mice subjected 30% TBSA back skin to the 90 oC water bath for 12 seconds is only 3-5%. To assess the protective activity of heparin on burned mice, we worsened the severity of injury by burning 50% TBSA at 90 oC for 15 seconds(we added 20% TBSA burn on the belly skin), which caused very high mortality on day of injury and increased with days after injury. The wild-type and knockout mice were injured with or without heparin treatment at 20mg/kg, twice a day, for seven days after the burn trauma. Kaplan-Meier survival curves were drawn and the differences between survival rates were compared by log-rank tests. There were 20 mice in each group. 
Histopathological Examination
      The mouse spleen specimens were fixed in 10% formaldehyde and then embedded in paraffin. 4 �m tissue sections were stained with hematoxylin and eosin (H&E). Two experienced pathologists, who were unaware of the treatment conditions, examined the slides under light microscopy to in order to detect the histopathological changes (6 mice in each group).
TUNEL stain 
      4 (m spleen sections were deparaffinized in xylene and dehydrated in graded ethanol. Apoptotic cells were identified using the Terminal Deoxynucleotidyl Transferase dUTP Nick-end Labeling (TUNEL) technique. The TUNEL-positive cells within the spleen white medulla were scored by randomly selected 10 fields of white medulla per animal. The selected fields were traced by the magnetic lasso tool in Adobe Photoshop CS4 Extended Version (Adobe Systems, San Jose, CA) for analysis. NIH Image J software (ver. 1.43, NIH, Bethesda, MD) was used for counting cells.
      The data was expressed as the percentage of TUNEL-positive cells/100 spleen lymphocyte in the white medulla. Digitized images were analyzed by two blinded investigators.
Time course study on the cellular apoptosis in spleen
      The burned mice were sacrificed at different time points to harvest the spleens (6hr, 12hr, 24hr, and 2d after the burn injury, 5 mice for each time point). We performed a TUNEL stain to detect the cellular apoptotic index at each time point.  We chose the time point which had the maximum apoptotic index for the present study.  
Western Blot Analysis
      The total spleen protein was isolated and concentrations for western blot were measured by the Bradford method. Identical amounts of protein from each sample were run through 10% SDS-PAGE solution and transferred onto an equilibrated polyvinylidene difluoride membrane by electroblotting. The membranes were incubated at room temperature for one hour with the primary antibodies IL-1� or IL-1�. The level of expression of the protein was normalized to the expression of GAPDH in the same sample. Bands were quantified by scanning densitometry using the digital Kodak Gel Logic 200 system (Carestream Molecular Imaging, USA). Time course study on the IL-1 expression in the spleen was performed at different time points (6hr, 12hr, 24hr, and 2d after the burn injury, 3 mice at each point). 
ELISA Analysis on IL-1 alpha and IL-1beta 
The mouse serum was prepared by centrifugation. Samples, including the standards of known Il-1 concentrations and unknowns are pipetted into the plate wells. The antigen was added to the wells fro the first incubation. After washing, a biotinylated monoclonal antibody specific to Il-1 alpha or Il-1 beta was incubated. Then the streptavidin-proxydase was added. After incubation and washing, the substrate solution was added to induce a colored reaction product.
We collected the serum at a series of time points: 0 hour, 2 hours, 4 hours, 8 hours, 16 hours, one day, 2 days and 3 days after the burn injury, to perform the time course study on the expression of IL-1 alpha and IL-1 beta.
Statistical Analysis
      All results are presented as MEAN�SEM. and examined by one- and two-way ANOVA. Individual group means were compared with Student's unpaired t test.  Survival analysis was performed by the Kaplan-Meier method. The differences in the survival rates were tested for significance by the use of a log-rank test. Differences with p-value of less than 0.05 were considered to be significant. 
Results
1. Burn induced significant apoptosis in the mouse spleen
    Histology of our cutaneous burn model showed a full-thickness burn of mouse skin demonstrating interrupted epidermal cell lining, damaged hair follicles, thickened and scarred dermal collagen layer (Fig.1. A,B). The H&E stain on the burned mice spleen showed almost normal histological structures. There were no significant gross or histological differences noticed between the sham and burned mouse spleen (Fig. 1. B, C). However, TUNEL stain on the sections of the spleens from the sham mice demonstrated diffusely scattered apoptotic cells at a rate of 3.6+/-2.1% in the white medulla. By contrast, burn induced significant cellular apoptosis in the spleen presented an apoptotic index of as high as 28.8+/- 5.9%. The majority of the apoptotic cells were present in the white medulla, suggesting they might be lymphocytes. Rare apoptotic cells were present in the red medulla of the spleens (Fig. 1. E, F).
      The time course study on apoptotic cells showed burn induced apoptosis as early as 6 hours after burn injury, after which the apoptotic index gradually increased to a maximum level at 24 hours, decreasing 2 days later.  As a result, we chose 24 hours after burn as the time point for the rest of our study (Fig. 1. G).
2. Burn induced IL-1 expression in serum and spleen
 	Expression of IL-1� and IL-1� in the spleen was mildly detectable in sham-treated mice. Thermal injured mice presented remarkably high IL-1� and IL-1� expression in the spleen. A time course study on this expression exhibited that the spleen presented the highest expression of both IL-1� and IL-1� at 24 hours after the thermal injury (Fig. 2.). ELISA analysis indicated that significant IL-1� and IL-1� expressions were detected in the serum as early as two hours after the burn injury, and both peaked on the first post-injury day (Fig. 2. D, E). Expressions of IL-1� and IL-1� presented earlier in serum than that in spleen. 
3. Heparin decreased the spleen apoptosis and increased the survival rate in burned mice  
     Mice treated with heparin displayed much less apoptotic cells in the spleen (8.6 +/- 3.4%). In contrast, the saline-treated and nontreated mice demonstrated significant apoptosis (28.7+/- 5.1%, p<0.001), which suggests a protective effect of heparin on the spleen cells from apoptosis. Heparin treatment did not change the pattern of apoptotic cell distribution, as most of the apoptotic cells were still present in the white medulla of the spleen (Fig. 3. A, B, C, D, E). Kaplan-Meier survival curves showed the mice treated by use of heparin had a survival advantage over the nontreated mice (P < 0.0056), indicating the protective role of heparin on the burned mice (Fig. 3. F). 
4. Heparin reduced IL-1 expression in the serum and spleen
	As previously stated, thermal injured mice showed significant IL-1� and IL-1� expression in the spleen.  Treatment with saline did not change the expression of IL-1 (IL-1� and IL-1�) in the serum and spleens of the burned mice.  However, when treated with heparin, the expression of IL-1 was greatly decreased in the burned mice serum and spleen. These results suggest that heparin reduced the burn-induced IL-1 expression in both the serum and spleen (Fig. 4.). 
5. IL-1Ra blocked the effect of heparin on burn induced spleen apoptosis
	When IL-1Ra was administrated to burned mice, there was less apoptotic cells detected in the white medulla. When IL-1Ra and heparin were both administrated to the burned mice, heparin treatment did not show a significant reductive effect on spleen apoptosis in addition to the reduction caused by IL-Ra treatment.  These results might suggest that IL-1 played a critical role in burn induced spleen apoptosis and in the effects of heparin treatment on spleen apoptosis (Fig. 5. A, B, and C).
6. IL-1 R KO mice showed less apoptosis in spleen and higher survival rate after severe burn injury
     When we performed the skin burn injury on the IL-1 R KO mice, we found that the thermal injury did not induce as much apoptosis in the white medulla as that in the wild type mice. Heparin administration did not significantly reduce the apoptotic index in the spleen of the IL-1R KO mice, either. These findings further suggest that IL-1 plays an important role in burn induced spleen apoptosis and heparin might decrease burn-induced spleen apoptosis through the IL-1 pathway in mice (Fig. 5. D). Kaplan-Meier survival curves showed the IL-1R KO mice and burned WT mice on IL-1Ra treatment had survival advantage over the burned WT mice (P < 0.001), and there was no significant survival difference between burned KO mice and KO mice treated with heparin and burned WT mice on IL-1Ra treatment (P >0.05), suggesting that IL-1 pathway plays an centrally important role in the protective role of heparin on the burned mice (Fig. 5. E).
Discussion
      Immune dysfunction after a burn injury might play a critical role in the introducing of infections in clinic, and immune cellular apoptosis might contribute to this post-burn immune dysfunction. We postulate that spleen dysfunction might be an important contributing factor to this post-burn infection. Treatment that can prevent this apoptosis may have clinical value in burn patients. In the present study, we evaluated the burn-induced cellular apoptosis in the spleen, and whether heparin has protective effects on spleen, while elucidating the underlying mechanism.  
      A few studies suggest that skin burn injury might induce apoptosis in remote visceral organs. 13 In our present study, we exposed the mice to a thermal injury comprising of 30% of the whole skin area and full skin thickness. We found that significant cellular apoptosis in the spleen could be detected as early as 6 hours post burn. At 24 hours post burn, as many as 28.8+/- 5.9% of the cells in white spleen medulla underwent apoptosis, which we postulate is significant enough to affect the immune function of spleen. Interestingly, rare apoptosis occurred in the red spleen medulla, indicating that a burn might mainly induce lymphocytes to undergo apoptosis in the spleen. It is unknown if this is also true in burn-injured human patients. As the thymus degenerates in humans over time, the spleen plays a very important role in human immune defenses. 14 Therefore, it is feasible that cellular apoptosis in the spleen might contribute to the vulnerability of infection in burn patients. 
      Current data shows that a skin burn induces significant secretion of cytokines and chemokines, 15 which may trigger or promote cellular apoptosis. Among these factors, the interleukin-1 (IL-1) family of cytokines (mainly includes two individual members: IL-1� and IL-1�) play a central role in the regulation of immune and inflammatory responses. 16 IL-1� and IL-1� rapidly increase messenger RNA expression of hundreds of genes, in multiple different cell types. In the present study, we found both IL-1� and IL-1� were significantly expressed in the mouse serum and spleen after a burn injury. The spleen presented the highest expression of IL-1 at 24 hours after the thermal injury, which interestingly coincided with the maximum apoptosis occurrence in the spleen.  Berda Haddad found that IL-1� expression mediates endothelial cell apoptosis under sterile inflammation. 17 Pauwels found that both IL-1� and IL-1� trigger apoptosis in  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/21622588"  cigarette smoke-induced pulmonary inflammation and COPD. 18 Our finding suggests that IL-1 plays a very active role in burn induced cellular apoptosis in the spleen white medulla after a burn injury. 
      In addition to heparin�s anti-coagulation activity, researchers found heparin might have several other significant properties including inhibition of smooth muscle cell proliferation, 19 prevention of trauma-induced vascular stenosis and hypoxia induced pulmonary hypertension. 20, 21 The underlying mechanism is still unknown. Yagmurdur showed heparin protects the gut endothelial cells from burn-induced apoptosis. 22 Anastase found heparin could inhibit lipopolysaccharide (LPS) induced cytokine production through inhibition of LPS-induced monocyte activation and the binding of LPS to cells via a CD14-independent pathway. 23 We found the spleens of burned mice, treated with heparin, underwent apoptosis much less than those not treated with heparin. This clearly suggests a protective effect of heparin on the spleen cells from burn-induced apoptosis. Data increasingly suggests that heparin possesses anti-inflammatory effects. So it is reasonable that heparin might decrease cellular apoptosis through its anti-inflammatory properties. In this present study, we found that heparin treatment to burned mice significantly reduced the burn-induced expression of both IL-1� and IL-1� in the mice serum and spleen, indicating that the IL-1 pathway may be involved in apoptosis occurrence and heparin-caused reduction in spleen.    
      Both IL-1 INCLUDEPICTURE "http://stke.sciencemag.org/math/alpha.gif" \* MERGEFORMATINET  and IL-1� have potent proinflammatory activities. For the most part, these two forms of IL-1 bind to the same cellular receptor: IL-1R. Interleukin-1 receptor antagonist (IL-1Ra) is a molecule that competes for receptor binding with IL-1� and IL-1�, blocking their role in immune activation. 24 When our burned mice were treated with IL-1Ra, there was much less apoptosis in the white medulla, further suggesting that burn injury induces spleen apoptosis by activating the IL-1 pathway. Moreover, we found that IL-1Ra blocked heparin�s reductive effect on apoptosis in these burned mice. This further indicates that IL-1 might be the pathway through which heparin decreases cellular apoptosis in the white medulla of the spleen.
      Although heparin has not been shown to have any clinical benefits in a 2007 clinical study with burn patients, 25 Our survival curve study on burned mice shows a significant decrease in mortality with heparin treatment, which suggests a clear protective property of heparin on burned mice. One possible interpretation of this difference is we treated the mice with much higher dose that could not be administered on patients due to likely heparin complications. When we exposed the IL-1 R KO mice to the thermal injury, these mice did not show as much apoptotic cells in their white medulla as that in wild type mice. Heparin administration to these KO mice did not significantly reduce the apoptotic index in the spleen. Moreover, our survival curve study presented that burned IL-1R KO mice have much less mortality than that in burned WT mice , and treatment with heparin did not has survival benefit in KO mice when compared with mortality in untreated burned IL-1R KO mice. These findings are consistent with each other, and clearly point toward the potential that IL-1 pathway is the mechanisms, at least partially, by which heparin reduces apoptosis in the spleen. IL-1 pathway plays a central role in extracellular and intracellular signaling, including activation of JNK and p38 nitrogen-activated protein kinase pathways, 26 which, cooperatively, induce the expression of canonical IL-1 target genes (such as IL-6, IL-8, MCP-1, COX-2, MKP-1) by transcriptional and posttranscriptional mechanisms. 27 Of note, most of these intracellular components participate in the cellular response of apoptosis. Heparin may act by significantly down-regulating centrally important IL-1 expression, inhibiting burn-induced spleen apoptosis in the mouse. 
      Collectively, our data suggests that burn injury induces significant cellular apoptosis and increases IL-1 expression in the serum and spleen. Heparin might have a previously unrecognized role in preventing this burn induced spleen dysfunction in mice. However, much is still unknown about the protective effects. It is unknown whether heparin affects IL-1 expression directly or indirectly, nor the kinds of lymphocytes that underwent apoptosis in the spleen white medulla after burn. The roles of other genes or factors that might be implicated in the heparin treatment have not been investigated. It is not clear if these results can be extrapolated to human studies. The underlying mechanism responsible for apoptosis reduction as a response to heparin treatment is not completely understood. More studies are still needed to clarify the underlying mechanism of burn induced apoptosis and heparin treatment. Clinical use of heparin as an anti-inflammatory agent has been held back for fear of excess bleeding, but this study strongly suggests a potentially important therapeutic application for heparin on burn patients in order to prevent spleen dysfunction and related infections. 
	In conclusion, our results show that burn induces significant cellular apoptosis and higher IL-1 expression in the mouse serum and spleen. Heparin inhibits burn-induced spleen apoptosis by suppressing the IL-1 expression in mice.
Acknowledgements: 
      This work was supported by the China National Nature Science Grant: No. 30472031 to Dr. Quancheng Kan. 

Abbreviations
TUNEL, Terminal Deoxynucleotidyl Transferase dUTP Nick-end Labeling; TNF-a, Tumor necrosis factor alpha; IL-1 R +/+, Il-1 receptor wild-type mouse; IL-1 R -/-, IL-1 receptor knock-out mouse; IL-Ra, IL-1 receptor antagonist; TBSA, total body surface area; H&E,  hematoxylin and eosin; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; DAB, 3,3�-diaminobenzine tetrahydrochloride. 

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. 
Figure Legends
Figure 1: Histology of the cutaneous burn model and burn induced remote spleen apoptosis. A. Histology of the normal mouse back and belly skin with a hematoxylin/eosin stain indicating an intact epi./12>BNOT�	
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OP��^_����Z\np����������䰦���������������������}�iV�$hiKh��0J3OJQJ^JmH	sH	'hiKh��0J3OJQJ\�^JmH	sH	hiKh��5�OJQJ^JhiKh��6�OJQJ^JhiKh��OJQJ^JhHS_OJQJ^J0h�;�B*OJPJQJ^Jeh@ph\\\r��@U0hec�B*OJPJQJ^Jeh@ph�r��@6h�q�h�;�B*OJPJQJ^Jeh@ph�r��@!dermal cell layer, hair follicles and sebaceous glands and normal keratinocytes and dermal collagen. B. Histology of full-thickness burn of mouse skin demonstrating interrupted epidermal cell lining, damaged hair follicles, thickened and scarred dermal collagen layer. C and D: Representative images of H&E � stained spleen sections.  C. The sham-treated mice exhibited normal spleen structure. D. Burn injury produced no significant changes to the spleen (WM: white medulla; RM: red medulla, n=5 animals per group, H.E X 200). E and F: Representative histological images of TUNEL-stained spleen sections. E. Occasional apoptotic cells were detected in the spleens of sham-treated mice. F. Significantly increased numbers of TUNEL-positive cells were found in the white medulla of the spleen in burned mice. Rare apoptotic cells were detected in red medulla of both sham and burned mice (n=5 animals per group). G. Time course of burn induced apoptosis in the spleen. Apoptosis were induced by burn injury as early as 6 hours after burn injury, after which the apoptotic index gradually increased to a maximum level at 24 hours, then decreased 2 days later. n=5 animals per group (sham vs. burn: *p<0.05, **p<0.001; within burn group: p<0.05).
Figure 2: Time course of IL-1� and IL-1� expression in the serum and spleen of burned mice. A. Western blot detection of IL-1� and IL-1� expression, each group: n=6 (the experiment was repeated three times). B. Level of IL-( expression normalized to the expression level of GAPDH (no difference exists among *groups and ** groups, P>0.05; *** P<0.05 v.s ** groups and * groups; ** P<0.05 v.s * group:). C. Level of IL-1� expression normalized to the expression level of GAPDH (no difference exists among *groups, P>0.05; ** P>0.05 v.s *** group; * groups v.s ** group and *** group v.s * group: P<0.05). D. Time course study on the expression of IL-1�. in the serum (ELISA). E.  Time course study on the expression of IL-1� in the serum (ELISA). Both showed significant increase of IL-1� and IL-1� since 2hours after burn injury (ANOVA, p<0.01 vs. sham). 
Figure 3: Effects of heparin on the cellular apoptosis in the spleen and on survival rate of burned mice. Representative histological images of TUNEL stained spleen sections. A. sham B. burned mice. C. Burned mice treated with saline. D. Burned mice treated with heparin. E. Percent apoptotic cells in each group. Mean ( SEM, n=5 animals per group. Burn injury induced significant cellular apoptosis in the spleen, and heparin significantly reduced the apoptotic index (*p<0.001 vs. ** groups; no difference exists among * groups and ** groups: p> 0.05).  E. Kaplan-Meier survival curves show the mice treated with heparin had a survival advantage over the nontreated mice (P < 0.0056), indicating the protective property of heparin on the burned mice. 
Figure 4: Effects of heparin treatment on IL-1( and IL-1� expression in burned mouse. A.  Western blots analysis of the effect of heparin treatment on IL-1( expression in mouse spleen (no difference in * groups or ** groups, but significant difference was demonstrated between * groups and **groups, P<0.05). B. Western blots analysis of the effect of heparin treatment on IL-1� expression in mouse spleen (no difference existed in * groups or ** groups, but significant difference was found between * groups and **groups, P<0.05). Burn injury increased expression of IL-1( and IL-1� in the spleen and this effect was abolished by treatment with heparin. C. ELISA test of IL-1( in serum. D. ELISA test of IL-1� in serum (No difference exists among * groups and ** groups, P>0.05 ; *P<0.005 v.s ** groups (n=5 animals with ea� Bdlp�������Tvx���   N P f ���˴�������ˠːˠn`M$h[(h[(6�B*OJQJ^Jph�h1�B*OJQJ^Jph�!h[(h1�B*OJQJ^Jph�!h[(h[(B*OJQJ^Jph�	ja�hiKh��OJQJ^Jh[(OJQJ^Jh�V�OJQJ^JhiKh�V�OJQJ^Jho�OJQJ^JhiKh��OJQJ^J$hiKh��0J3OJQJ^JmH	sH	'hiKh��0J3OJQJ\�^JmH	sH	f h r t � � � � � � � � � � !n!r!�!�!��ν���ί���xa�P?1hLaB*OJQJ^Jph�!h[(hLaB*OJQJ^Jph�!h3h[(B*OJQJ^Jph�-h3h��0J3B*OJQJ^JmH	ph�sH	0h3h��0J3B*OJQJ\�^JmH	ph�sH	!h3h��B*OJQJ^Jph�hiKh��OJQJ^Jho�B*OJQJ^Jph�!h[(h[(B*OJQJ^Jph�h1�B*OJQJ^Jph�!h[(h1�B*OJQJ^Jph�$h[(h1�6�B*OJQJ^Jph��!�!�!�!�!�!�!�!�!�!�!�!"&"0"^"`"l"p"v"~"�"�"�"��ͺ������੖��tct�J0h3h��0J3B*OJQJ\�^JmH	ph�sH	!h3h�L�B*OJQJ^Jph�!h3ho�B*OJQJ^Jph�!h3h��B*OJQJ^Jph�$h3h[(6�B*OJQJ^Jph�!h3h[(B*OJQJ^Jph�$h[(hLa6�B*OJQJ^Jph�$hLahLa6�B*OJQJ^Jph�hLaB*OJQJ^Jph�!h[(hLaB*OJQJ^Jph��"�"�"�"�"�"##T#X#^#n#x#�#�#�#�#�#�#�#�#$$�Ѻ��є�j�Y���@у@у��0h3h�L�0J3B*OJQJ\�^JmH	ph�sH	!h3h��B*OJQJ^Jph�0h3h��0J3B*OJQJ\�^JmH	ph�sH	!h3h�L�B*OJQJ^Jph�)h3h��B*OJQJ^JnHph�tH!h3h3B*OJQJ^Jph�-h3h30J3B*OJQJ^JmH	ph�sH	-h3h�L�0J3B*OJQJ^JmH	ph�sH	-h3h��0J3B*OJQJ^JmH	ph�sH	$$$!$"$,$1$4$>$y$}$�$�$�$�$�$�$�$%%%% %!%"%(%�����齯�������wiwXwXN�A�h�6�h�6�OJQJ^Jh�6�OJQJ^J!h�	Hh�6�B*OJQJ^Jph�h�V�B*OJQJ^Jph�!h�	Hh��B*OJQJ^Jph�hiKh�6�OJQJ^JhiKh.>6OJQJ^JhiKh��OJQJ^JhiKh��5�OJQJ^J!h3h�L�B*OJQJ^Jph�hiKh�V�6�OJQJ^JhiKh�V�OJQJ^Jh�V�OJQJ^Jh�V�h�V�OJQJ^J(%:%C%D%G%s%t%	&&&& &$&=&U&V&X&\&^&`&c&�&�&�&�&�&�&�&�&�&�&������ܻ����������yly_lyl�lylyhiKhrT�OJQJ^JhiKh�6�OJQJ^JhiKh.>6OJQJ^J!h�Ih�IB*OJQJ^Jph�!h�Ih!�B*OJQJ^Jph�$h�Ih��6�B*OJQJ^Jph�!h�Ih��B*OJQJ^Jph�	j��hiKh��OJQJ^JhiKh��OJQJ^Jh�6�OJQJ^JhiKh�6�OJQJ^J�&�&�&�&#'&'0'T'U'((�(�(�(�()d)�)�)�)�)�)�)�)�)�����ƹ��������qcqcqcPcq$hj5�hj5�6�B*OJQJ^Jph�hj5�B*OJQJ^Jph�!hj5�hj5�B*OJQJ^Jph�hj5�OJQJ^Jh�BGOJQJ^J$hiKh��0J3OJQJ^JmH	sH		ja�hiKh��OJQJ^JhiKh��OJQJ^JhiKh��5�OJQJ^JhiKh.>6OJQJ^JhiKhrT�OJQJ^J"hiKh.>60J#5�6�OJQJ^J�)�)�*�*�*�*�*�*0+x+�+�+�+�+�+�+�+,
,,,�,�,�,�,-����ij��������������xgSg'	ja�h��h�udB*OJQJ^Jph�!h��h�udB*OJQJ^Jph�h�udOJQJ^J	ja�hiKh��OJQJ^J$hj5�hj5�6�B*OJQJ^Jph�hj5�B*OJQJ^Jph�!hj5�hj5�B*OJQJ^Jph�hj5�OJQJ^J$hiKh��0J3OJQJ^JmH	sH	hiKh��OJQJ^J!hj5�h��B*OJQJ^Jph�-�-�-�-�-�-�-.@
@@@Y@Z@_@`@�@�@�@�@�@�@�@��辫�����ylbUbUbK>KUKhiKhfOJQJ^JhfOJQJ^JhiKh nOJQJ^Jh nOJQJ^JhiKh��OJQJ^JhiKh��5�OJQJ^J!h��h�h.B*OJQJ^Jph�U!h��h��B*OJQJ^Jph�$h��h�ud6�B*OJQJ^Jph�!h��h�udB*OJQJ^Jph�0h��h�ud0J36�B*OJQJ^JmH	ph�sH	-h��h�ud0J3B*OJQJ^JmH	ph�sH	ch group).
Figure 5: Effects of IL-1Ra and IL-1R KO on heparin treatment to burned mice. A and B: Representative images of H&E � stained spleen sections.  A. Burned mice treated with IL-1Ra exhibited no gross changes to spleen structure. B. Burned IL-1KO mice produced no significant changes to the spleen (WM: white medulla; RM: red medulla, n=5 animals per group, H.E X 200). C. Effects of IL-1Ra on heparin treatment to burned mice. Burn injury induced marked spleen apoptosis (t test, *p<0.001 vs. sham). Heparin administration significantly reduced the apoptotic index, and this effect could be partially blocked by IL-1Ra (ANOVA, **p<0.01 vs. burn).no difference exists among * groups, ** groups and *** groups: P>0.05. D. Effects of IL-1R KO on heparin treatment to burned mice. Burned IL-1 R KO mice did not present as much apoptosis as that in burned wild type mice. Heparin did not significantly reduce the apoptosis in the spleen of the burned IL-1R KO mice (ANOVA: *p<0.001; **p>0.05). E. Kaplan-Meier survival curves showed the IL-1R KO mice had survival advantage over the WT mice (P < 0.001), and there was no significant survival difference between burned KO mice, burned WT mice treated with IL-Ra and KO mice treated by use of heparin (P >0.05), which indicated that IL-1 pathway played an important role in the protective property of heparin on the burned mice. 










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