An overwhelming inflammatory response represents the “bad” side of the double-edged sword of host defense. Multiple organ dysfunction syndrome (MODS), the maladaptive outcome of systemic inflammation, remains a leading cause of death in the intensive care unit. Clinical and experimental studies performed over the past several decades have implicated that bacterial and endotoxin translocation from the gut to distant organs plays an important role in the pathogenesis of MODS (1, 2). Gut injury may be a contributor to the systemic inflammatory response in critical ill patients.
Mast cells are ubiquitously identified cells that have been recognized participants in the human inflammatory response. Mast cell heterogeneity in humans and rodents has been intensely investigated. In rodents, mast cells are classified as intestinal mucosa mast cells (IMMC) and connective tissue type mast cells according to their tissue site (3). Interestingly, intestinal mast cells in humans and rodents are distributed in perivascular and perineuronal areas. The close association of mucosal mast cells with blood ± vessels and enteric nerves has morphological and functional consequences (4). IMMC were identified as one of the five initiators of the microcirculatory hypothesis of MODS. Their participation in acute vasodilation, chemokine production and leukocyte trafficking, proinflammatory cytokine signaling, degradation of the extracellular matrix, and immunomodulatory and counterinflammatory signaling has been widely accepted (5-8).
Somatostatin (SST), a multifunctional neuropeptide, is widely distributed in the central nervous system and peripheral tissues. In the gastrointestinal tract, SST has been found in the stomach, duodenum, jejunum, ileum, and colon, as well as in the pancreas. Since its characterization three decades ago, the tetradecapeptide SST has attracted much attention because of its wide variety of biological functions. Recently, Ferrer et al. (9) reported that SST could improve the course of MODS caused by hypoxia-reperfusion of the gut. The mechanisms behind this may be complicated. The physiological actions of SST are initiated with its interaction with specific membrane-bound, high-affinity receptors on the surface of responsive cells. Five subtypes of SST receptors (SSTR), SSTR-1 to SSTR-5, have been cloned and functionally characterized (10).
The objective of this study was to observe the effects of SST on activation of IMMC during MODS, and to speculate on the pathogenesis of MODS in view of the interaction between gut peptides and mucosal immunity.
MATERIALS AND METHODS
Animal model of MODS
A rat MODS model was established by an intraperitoneal injection of zymosan (11). Adult male Wistar rats (weighing 250-300 g, provided by the experimental animal center of Sichuan University) were fed with standard rodent chow (protein offered 20% calorie of total) and drank freely before the experiment. One gram of zymosan (Sigma, St. Louis, MO) suspended in 40 mL of medical paraffin was boiled for 60 min at 100°C, and was stored at 4°C until use. The rats were inoculated intraperitoneally with zymosan at a dosage of 75 mg/kg. Indications of the established model included the manifestations of multiple organ dysfunction occurred 24 h after infliction of injury; pathological changes characterized by acute inflammatory injury in vital organs; the function of multiple organs deteriorated, while blood cultures remained sterile; and the experiment could be repeated with similar results carrying about 35% mortality (11-13). This animal experiment was approved by the Experimental Animal Review Board of Sichuan University.
Thirty Wistar rats were divided into five groups: normal control group, no MODS, treated with saline only; MODS control group, MODS established as described above, treated with saline alone; MODS + low SST group, SST at dosage of 0.023 ng/kg/h; MODS + high SST group, SST at dosage of 2.3 ng/kg/h; and normal control + SST group, no MODS, treated with SST at a dosage of 2.3 ng/kg/h. Each group consisted of six animals. Thirty minutes after intraperitoneal inoculation of zymosan, SST in normal saline was injected intravenously via the tail vein with syringe pump (B. Braun Co., Kronberg, Germany). SST injection continued approximately 25 h while 10% amobarbitaum was given intraperitoneally at dosage of 100 mg/kg every 6 h. After 25 h, injections were stopped, the rats were killed by shed blood, and the whole small intestine and other vital organs were removed.
Determination of histamine and TNF-α concentration
The intestinal lumen was cleaned with saline. The digested intestinal mucosa was made into homogenized suspensions. Total protein level was determined by Coomassie Blue assay, and the histamine level in the plasma or intestinal tissue suspensions was measured by fluorescent assay (14). Histamine concentration in the plasma was expressed in nanograms per milliter, whereas that of the intestinal tissues suspension was normalized to nanograms per gram of protein by calculation of the ratio of the total histamine to the total protein level.
TNF-α concentration was determined by using rat TNF-enzyme-linked immunoabsorbant assay (ELISA) kit (Sigma). The units used to express serum TNF-α was picograms per milliliter, and the TNF-α concentration in the small intestines was calculated based on amount of TNF-α to total proteins, and was expressed in terms of picograms per gram of protein.
Morphological and functional evaluation of key organs
Specimens from the vital organs such as small intestine (5cm from the distal end of the ileum), liver, kidney, heart, and lungs were taken out and fixed with 10% formaldehyde. The paraffin sections were stained with hematoxylin and eosin for histological evaluation in a single blinded fashion. For semiquantitative evaluation of lesions, 10 arbitrary microscopic fields were viewed in each sample. The scoring system was based on area of the lesion: +, <1/3 total area; ++, 1/3-2/3 total area; +++, >2/3 total area.
Peripheral blood was taken from each group of rats before they were killed to determine the oxygen partial pressure (PO2) with DMNI modular system (AVL, Graz, Austria), alanine aminotransferase (ALT), and creatinine levels (AUOLYMPUS 5400; Olympus, Tokyo, Japan).
Observation of ultramicrostructures in IMMC from MODS rats
Small-tissue specimens from the intestine were immersed in 4% glutaraldehyde for 2 h. The specimens were fixed for 1 h in 1% osmium tetroxide and were then dehydrated in graded acetone solutions, contrasted in a mixture of 1% phosphotungstic acid and 0.5% uranyl acetate, and embedded in epon 812. Ultrathin sections (60-80 nm) were cut on an MK III Ultrotome (LKB Instrument, Gaithersburg, MD), routinely contrasted with uranyl acetate and lead citrate. Under transmission electron microscope, IMMC can be identified by many 0.5- to 1.0-μm cytoplasmic granules. For semiquantitative evaluation of degranulation of IMMC, six random IMMC were viewed in each sample. The scoring system was based on the vacuole area: +, <1/3 total cell; ++, 1/3-2/3 total cell; +++, >2/3 total cell.
Procedures for IMMC isolation
The small intestine was removed from rats and fecal material was flushed off with 300 mL of saline. The mesentery and adherent connective tissue and fat were dissected from the intestine and the Payer's patches were removed. The intestine was opened longitudinally and cut into 3- to 5-cm pieces, which were immersed in 50 mL of Hanks' balanced salt solution (HBSS) containing 25 mM HEPES, 5% fetal bovine serum (FBS), pH 7.2 to 7.4, for 15 min. The washed intestine was cut into 1- to 3-mm pieces and was washed three times for 10 min using a magnetic stirring apparatus in 50 mL of Ca++- and Mg++-free HBSS containing 25 mM HEPES and 1.3 × 10−4 M EDTA as a disodium salt to remove epithelial cells. Finally, the tissue was incubated with stirring in 100 mL of HBSS containing 25 U/mL collagenase I (Sigma) for 60 min at 37°C. The supernatant was decanted and the remaining tissue in 20 mL of RPMI-1640 (Pharmacia, Uppsala, Sweden) was mechanically disrupted by repeated syringing. The resulting suspension was rapidly filtered through 10-mL syringes containing 300 mg of loosely packed nylon wool. These lamina propria cells were resuspended in 10 mL of RPMI-1640 (15).
Procedures for IMMC purification
Cell suspensions (1 × 107 cells) were enriched for IMMC by layering in 10 mL on discontinuous density gradients of Percoll (Pharmacia) plus 10% FBS and 10 mM HEPES (adjusted to pH 7.4, 300 mosmol/kg). These were spun in a refrigerated centrifuge at 600g for 20 min. The bottom layer of cells (2-3 × 106 cells) was collected and identified by toluidine blue staining for identifying IMMC (16) or hematoxylin and eosin staining for identifying remaining cells.
Effects of SST on the activation of IMMC in normal rat in vitro
The yield of viable IMMCs from six normal Wistar rats was recovered in HEPES (10 mM)-Tyrode's and was divided into control and SST groups. IMMCs (1 × 106 cells) in each group were incubated with SST in the concentration range of 1 × 10−5 mol/L to 1 × 10−9 mol/L or without SST, at 37°C for 15 min. The reaction was terminated with 2 mL of cold Tyrode's. After trichloroacetic acid precipitation, the histamine concentration in IMMC and their supernatant were determined by fluorescent assay. The histamine release rate = histamine in supernatant/(histamine in supernatant + histamine in cells) × 100%. Furthermore, IMMCs treated with or without SST were fixed with 4% glutaraldehyde for 2 h, fixated with 1% osmic acid for 1 h, and sectioned into ultrathin slices for observation of ultramicrostructures in IMMCs under a transmission electron microscope.
Reverse transcriptase (RT)-PCR of the receptors for SST in IMMC
Total RNA was extracted from IMMC using the Tripure RNA isolation kit available from (Roche, Burlington, NC). First-strand cDNA was produced by Moloney murine leukemia virus reverse transcriptase (MBI, Fermentas, Vilnius, Lithuania) with 1 μg of total RNA and 0.5 μg of Oligo(dT)18. PCRs for SSTR-1, SSTR-3, and β-actin were carried out in a final volume of 50 μL containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, 2.5 U of Taq DNA polymerase (Shenggong, Shanghai, China), 10 mM of each dNTP, 5 μL of cDNA, and 25 mM of sense and antisense primers. The sense and antisense primers for SSTR-1 were 5′-GCTGGGATGTTCCCCAATGGCA-CC-3′ and 5′-CTCAAAGCGTGCTGATCCTGGAAG -3′, respectively, the sense and antisense primers for SSTR-3 were 5′-ATCCCTGCCATGGCCGCTGTTACC-3′ and 5′-GAAGGTTCTTACAGATGGCTCAGC -3′, respectively, and the sense and antisense primers for β-actin were 5′-GACTACCTCATGAAGATCCT-3′ and 5′-GCGG-ATGTCCACGTCACACT-3′, respectively. All the sense and antisense primers were offered by (Shenggong). GeneRuler 100-bp DNA Ladder Plus was purchased from Fermentas, Inc. (Shengzhen, China). After denaturation of the samples at 94°C for 10 min, PCR was carried out for 35 cycles consisting of denaturation at 94°C for 1 min, annealing for 1 min at 60°C, and extension at 72°C for 2 min. The amplification was terminated by a final extension step at 72°C for 10 min (17). The positive control was from a gastrinoma sample.
All quantitative data were presented as mean ± SD and were analyzed using Statistical Package for the Social Sciences for Windows software (SPSS, version 10.0; SPSS, Inc., Cary, NC). After being tested for squared differences, Student's t test was applied to both groups of specimens. Significance was set at P < 0.05.
SST arrests pathological changes of vital organs in rats with MODS
All experimental animals injected with zymosan developed into MODS. Mortality (33.3%) happened in the MODS control group and the MODS + low SST group. No rat in the MODS + high SST group, the normal control group, and the normal control + SST group died before they were killed. The impairments of vital organs, including the lungs, liver, intestines, and kidneys, in MODS rats were obvious when compared with the normal control group. Semiquantitative evaluation showed that inflammatory lesions of the distal end of the ileum, liver, lung, and kidneys in the MODS control group were all scored as +++.
The significant improvements of pathological changes were observed in the rats with MODS after intravenous injection of SST at 2.3 ng/kg/h (Fig. 1). The restraint of development in intestinal histopathological damages included alleviation of intestinal villi atrophy and severity of tissue edema, reduction in inflammatory cell infiltration, and less hemorrhage of intestinal mucosa. The hepatic lobular structure became more defined with less infiltration of inflammatory cells. It also showed a reduced loss of epithelial cells on the renal tubules with less tubular structure formation. Interalveolar spacing tissue appeared much thinner with decreased inflammatory cells infiltration and hyperemia. The lesion scores of these vital organs also decreased to +. Animals in the MODS + low SST group did not show much improvement of impairment in the vital organs. When compared with the normal control group, no histopathological changes were found in the rats of the normal control + SST group.
SST improves the function of vital organs in rats with MODS
After intravenous infusion of SST at dosage of 2.3 ng/kg/h, plasma ALT and creatinine decreased by 53% and 60%, respectively, and blood PO2 pressure increased by 50% (P < 0.05, Fig. 2), indicating a significant improvement of function of liver, kidney, and the lungs when compared with the control group. On the contrary, no significant change of functional parameters of the key organs in rats with MODS after infusion of SST at 0.023 ng/kg/h was observed (P > 0.05, Fig. 2). All of those vital parameters in the rats of the normal control + SST group were about the same as those of the normal control group (P > 0.05, Fig. 2).
SST increases the level of intestinal histamine in rats with MODS
No significant changes of the peripheral serum histamine levels were observed in rats with MODS after intravenous infusion of high doses of SST (P < 0.05), but the intestinal histamine level was significantly increased in the group with infusion of SST at dosage of 2.3 ng/kg/h (MODS control versus MODS + high SST = 8.60 ± 0.50 ng/g protein vs. 14.50 ± 1.08 ng/g protein, P < 0.01). Compared with MODS control, no significant changes were observed in the peripheral and intestinal histamine levels of rats given with low dosage of SST, P > 0.05 (Table 1).
SST decreases the levels of intestinal TNF-α in rats with MODS
Between groups of MODS control and MODS + low SST, TNF-α levels in peripheral blood and intestines showed slight differences (P > 0.05). When SST dosage was increased to 2.3 ng/kg/h, TNF-α levels in the small intestines were significantly decreased compared with the MODS control group, P < 0.01 (Table 1).
SST reduces degranulation of IMMC in rats with MODS
The vacuole area scored as “+” was observed in about 80% of IMMCs from rats of the MODS + high SST group, whereas about 75% IMMCs were scored as ++ to +++ in rats of the MODS control or the MODS + low SST group (Fig. 3). SST at a higher dosage considerably reduced degranulation of IMMCs in rats with MODS.
SST inhibits the activation and degranulation of IMMC in vitro
The purification rate of IMMCs was enhanced to 70%. SST at the concentration of 1 × 10−5 mol/L drastically decreased the release rate of histamine (2.54% ± 0.84%) when compared with the spontaneous release rate of histamine from IMMCs (22.86% ± 3.22%, P < 0.001). With regard to vacuolization, IMMCs in control group could be scored as “+.” However, rare vacuoles were found in IMMCs incubated with SST in vitro (Fig. 4). In the 1 × 10−5 to 1 × 10−9 mol/L concentration range, the inhibitive effect of SST on the histamine release rate of IMMC was negatively correlated to its concentration (r = −0.991, P < 0.01, Fig. 5).
IMMC expressed mRNA of SST-1
Only one SSTR-1 PCR product was found in IMMC of rats (Fig. 6). The bands between 310 bp and 613 bp were cDNA for β-actin (313 bp). The bands between 1078 bp and 1353 bp were cDNA for SSTR-1 (1183 bp). No SSTR-3 PCR product (447 bp) presented in the lanes.
Critically ill patients are susceptible to injury of the intestinal mucosa, changes in gut permeability, and failure of intestinal defense mechanisms. These conditions put the patients at risk for infection and MODS (18). However, inflammation of the gastrointestinal tract may be partly mediated by gut peptides or neurotransmitters (19-21). SST is involved in the negative control of the normal function of a number of organ systems. The inhibitory tissue factor mainly prevents local overreaction from a multitude of stimulatory factors. As a neurotransmitter, SST suppresses many inflammatory agents, such as IL-1, IL-6, and TNF-α, during the inflammatory process, likely in a paracrine fashion (22, 23). With regard to the effects of SST on MODS, controversial results were reported from several groups. Heuser et al. (24) reported the detrimental effects of octreotide on intestinal microcirculation. However, octreotide could reduce the severity of histopathologic changes and hemodynamic shock in early taurodeoxycholate-induced experimental pancreatitis (25). MODS induced by reperfusion after intestinal hypoxia could be prevented by SST (9). The therapeutic effects of SST on the inflammatory response of the intestine after intestinal ischemia-reperfusion injury are also interesting (26). Intravenous injection of exogenous SST in the initial stage of MODS successfully protected vital organs from severe inflammatory damages in pace with maintenance of corresponding functions in this study. The well-preserved histological composition of liver and small intestine, the two key immune organs, may afford a good basis to withstand the second insult in the process of trauma or stress. Also, these impressive results suggest that SST in appropriate dosage given in early phase of inflammation may be of benefit to critically ill patients.
We have proven that SST could inhibit activation and degranulation of IMMC in vitro in this study. The dose-dependent effects of SST on IMMC in vitro indicated a direct action of SST on IMMC and might explain the response of high or low dosage of SST in vivo. The physiological actions of SST are initiated with its interaction with specific membrane-bound, high-affinity receptors on the surface of responsive cells. Normally, SST binding induces a conformational change in the receptor that results in activation of an associated heterotrimeric G protein complex leading to exchange of GTP for GDP on the α-subunit (27). In the present study, mRNA for SSTR-1 was expressed in IMMC of rats. Thus, the mechanism behind the effect of SST on MODS development may be mediated through SSTR-1 on IMMC and results in sequential direct suppression on IMMC degranulation. A recent study also indicated that SST diminished IMMC activity through decreasing rat mast cell protease II (28). The evidence that SST targeted on IMMC, one of the initiators of MODS, addresses the necessity of using exogenous SST in early phase of inflammation. The heterogeneity of SST receptors has been proven during the last 10 years by the cloning of different genes coding for SST receptor subtype (23). SST-28 and SST-14 are nonselective ligands for all SST receptor subtypes. Short synthetic SST analogs, however, such as octreotide and lanreotide, demonstrate specific binding only for the subgroup consisting of SSTR-2, SSTR-3, and SSTR-5. No mRNA for SSTR-3 on IMMC was detected in this study. The direct effect of octreotide on IMMC is still uncertain unless mRNA for SSTR-2 or SSTR-5 are identified on these cells.
Once activated, the mast cells release a pleiotropic array of varied secretory products. They may act as inflammatory mediators or enzymes. Among the stored cell products within the cytoplasmic granules, histamine is the most important mediator. Histamine released from IMMC has a very short biologic half-life (a few minutes) before it is metabolized to several possible end-products. Therefore, it acts in a paracrine fashion. The quantitative changes of histamine from IMMC can not be reflected by its circulatory level. The lower concentration of histamine in intestinal mucosa during MODS compared with that in MODS treated with high dosage of SST reflects that histamine released from IMMC has been metabolized. SST arrested IMMC degranulation and resulted in higher concentration of histamine in intestinal mucosa. The dose-dependent effects of SST on histamine release elucidated the mechanism behind the MODS prevention with SST in this study. The biologic effects of histamine are numerous. The vasodilation effects of histamine similarly result in increased microvascular permeability and edema formation. Selectin activation on endothelial cells by histamine facilitates the “rolling” phenomenon of leukocyte on the endovascular surface to initiate the process of margination (6, 29).
The proinflammatory cytokine, TNF-α, has been shown to be synthesized and released by mast cell after activation. Increasing evidences indicate that TNF-α is an important mediator involved in activating the cascade of inflammatory reactions (30) through acute vasodilation, chemokine production, leukocyte trafficking, proinflammatory cytokine signaling, and degradation of the extracellular matrix (5). When degranulation of IMMC was inhibited by SST in the present study, the intestinal level of TNF-α was significantly decreased. Successively, severe inflammatory injury of intestinal mucosa did not happen. It is worth noting that the intestinal and hepatic histological changes usually synchronized with those of remote vital organs in this study. As a result, we may regard the gut as the central organ in systemic inflammatory response (31, 32). The well-organized barrier of gut might protect other vital organs from the inflammatory damages and keep their functions well. The serum level of TNF-α in the MODS + high SST group was a little lower than that of the MODS control group, but without any significance. The circulatory level of TNF-α may not be as sensitive as gut to SST treatment because it is affected by more complicated factors. Moreover, the change of intestinal level of TNF-α preceded the TNF-α alteration in serum during the development or prevention of MODS. This suggests that gut-derived TNF-α plays a more crucial role in the development of MODS.
MODS induced by zymosan usually experienced three phases (33). The first is acute phase or acute inflammatory phase (occurs in the first 24-48 h) associated with an early mortality. There is then a recovery phase followed by the third MODS phase and with a second peak of mortality (this third phase occurs 10-14 days after intraperitoneal zymosan). Goris's group considered that interventions should preferentially be targeted against multiple cytokines, and at least in this model, there may be a treatment window well after the initial challenge (33). Although we do not know what the effects of SST on MODS induced by zymosan in the third phase would be, extinguishment of a general inflammation at initial stage with SST may be an effective intervention for successive events. MODS is not only attributed to bacterial infection but also to severe inflammation. The zymosan-induced nonseptic model fulfills the criteria for MODS. This animal model displays a number of features encountered in human MODS and appears suitable to be used in intervention studies (12). Although limitation of development of MODS by SST is only observed in zymosan model now, mast cells targeted by SST have been taken as involved in all types of inflammation (34, 35). It suggests that SST may also be tried in MODS induced by other factors.
Based on the results of this study, we conclude that suppression of IMMC activity may be the important mechanism of the protective effects of SST on rat MODS model.
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Multiple organ dysfunction syndrome; intestinal mucosal mast cells; somatostatin; histamine; tumor necrosis factor-α