the most common cause of multiple organ dysfunction syndrome ( mods ) in obstetric patients is postpartum bleeding followed by gestational hypertension syndrome [ 1 , 2 ] . bleeding - induced multiple organ dysfunction syndrome ( bmods ) is a rapidly progressive disease that commonly occurs in critically ill obstetric patients with a high mortality rate . it is also one of the major causes of death in the maternity intensive care unit ( icu ) . bmods induces diffuse ischemia and functional impairment in multiple organ systems and , in severe cases , can progress to diffuse intravascular coagulation ( dic ) . for this reason , patients with a history of heavy blood loss during delivery should be monitored in the icu . it selectively binds to presynaptic 2-adrenergic receptors ( 2ar ) on the locus coeruleus and decreases the levels of norepinephrine release , resulting in a reduction of postsynaptic adrenergic activity . in the periphery , 2ars are widely distributed in many organs , including the liver , kidney , pancreas , blood vessels , and platelets . the administration of dex causes various effects in different organs [ 5 , 6 ] . currently , the primary clinical use of dex is for its effects on the central nervous system , such as short - term sedation and antianxiety . the pharmacological actions of dex in other organs have not been fully evaluated in clinical patients . in animal studies , dex has been shown to reduce mortality rates and inhibit inflammatory responses in endotoxemic rats without adverse effects on functions , such as respiration [ 8 , 9 ] . however , the benefits of applying dex to treat postpartum bmods in maternity icu patients have not been demonstrated due to the lack of a proper animal model . in a pilot study , a. sezer et al . found histopathological changes during sepsis - induced hypotension in rats . in another study , liver and pancreatic dysfunctions were observed following the clamping of the superior mesenteric artery . in the present study , the effects of dex on postpartum bmods were studied in rats in which bmods was induced by the combination of hypotension and clamping of the superior mesenteric artery . we demonstrated that dex administration reduced cytokine release and lung injury during postpartum bmods in rats . ( lake forest , il , usa ) . for reverse transcription polymerase chain reaction ( rt - pcr ) analysis , rnaiso plus , and taq dna polymerase were purchased from takara biotechnology co. , ltd . ( dalian , china ) . the revertra ace was purchased from toyobo biotech co. , ltd . sprague - dawley ( sd ) rats ( 20 adult male and 40 adult female , 200250  g ) were purchased from the animal center of guangdong province . the rats were housed in the guangzhou animal center in accordance with the specific pathogens animals standard with a 12  hr light / dark cycle . the animal studies in the present experiment were approved by the animal use and care committee of guangzhou medical university . the male and female ( 1  :  2 ) rats were allowed to mate in the cage until the females were pregnant , as determined by detecting sperm in vaginal secretions using microscopy , at which point the females were separated from the males until delivery . a total of 40 experimental female rats were randomly assigned into four groups , with 10 rats per group as follows . the sham ( s ) group : catheters were placed in the right femoral artery and the left femoral vein ;  s+c group : bleeding - induced hypotension and clamping of the superior mesenteric artery were performed ;  s+c+d2.5 group : administration of dex ( 2.5  g / kg / h )   to s+c rats ;  s+c+d5.0 group : administration of dex ( 5.0  g / kg / h )   to s+c rats . s+c group : bleeding - induced hypotension and clamping of the superior mesenteric artery were performed ; s+c+d2.5 group : administration of dex ( 2.5  g / kg / h )   to s+c rats ; s+c+d5.0 group : administration of dex ( 5.0  g / kg / h )   to s+c rats .   for the s group , the rats were anesthetized by the intraperitoneal administration of 10% hydration chlorine aldehyde ( 0.4  ml/100  g ) . the rats were then placed supinely on an animal surgical table with a heating pad . the body temperature was maintained at 3638c throughout the experiment . to monitor blood pressure , a polyethylene catheter ( pe-50 ) all of the catheters used in the present experiment were prepared with heparin to prevent blood clotting . for the s+c group , hypotension was induced by drawing blood from the right femoral artery into a glass syringe that was preloaded with heparin for temporary storage until the mean arterial pressure ( map ) reached the target level of 4550  mmhg . the map was constantly maintained at this low blood pressure level for 60  min by the withdrawal or reinfusion of storage blood via the right femoral artery . resuscitation was performed by re - infusing the full amount of blood that was previously taken from the rats to restore normal blood pressure . after a normal blood pressure was maintained for more than 30  min , the abdomen of the rat was opened under sterile conditions . the superior mesenteric artery was clamped for 60  min and then released . for the s+c+d2.5 and 5.0 groups , dexmedetomidine ( 2.5  g / kg / h and 5.0  g / kg / h , resp . ) was administered via the left femoral vein for 4 hours . after the previous experiment , the abdominal incision was sutured , and the catheters were removed . the rats were placed back in the cage and freely allowed to reach for food and drinking water . a 0.5-ml blood sample was taken from the abdominal aorta for immediate arterial blood gas level measurement . the left lung was harvested , immediately snap frozen in liquid nitrogen , and stored in the freezer for later histological and cytokine analyses . the changes in pulmonary , liver , and kidney functions were evaluated in bmods - induced rats by measuring arterial blood gas , aminotransferase ( ast ) , alanine aminotransferase ( alt ) , total bilirubin ( tbil ) , blood urea nitrogen ( bun ) , creatinine , and creatine phosphokinase ( cpk ) . morphological changes in the lung were evaluated using the index of quantitative assessment of histological lung injury ( iqa ) and alveolar interval thickness ( ait ) [ 15 , 16 ] . lung injury was considered to be the presence of alveoli - containing erythrocytes or two or more neutrophils . the ait from the lung was examined under the 200x power field using the ims image analysis system ( shenteng information technology co. , ltd . , six fields were randomly selected from each power field and examined , making sure to avoid the bronchial and blood vessels . total rna was purified using the trizol kit ( takara co. , ltd . ) . for the first strand cdna synthesis , rna ( 2  g ) was converted to cdna using superscript ii reverse transcriptase ( invitrogen ) . one microliter of reaction mixture was amplified by taq dna polymerase ( takara co. , ltd . ) in a thermal cycler ( geneamp , pcr system 2700 , applied biosystems , foster city , ca , usa ) . the first incubation was performed at 94c for 3  min for initial denaturation , and the following steps were repeated 30 times : 30 s at 95c ( denaturation ) , 1  min ( specific annealing temperature for each primer ) , and 1  min at 72c ( extension ) . the sequences for the primers used in the present study are as follows : il-4 : sense 5-tccttcacggcaacaaggaac-3 and antisense 5-gtgagttcagaccgctgaca-3 ( predicted size : 168  bp , annealing temperature : 50c ) ; ifn- : sense 5-gaactggcaaaaggacggta-3 and antisense 5-ggatctgtgggttgtt cacc-3 ( predicted size : 215  bp , annealing temperature : 49c ) . the pcr products were size - fractioned by 1% agarose gel electrophoresis . after staining with ethidium bromide , the amplified dna bands were analyzed with the image analysis software scionimage ( scion corp . the statistical analysis was performed using statistical package from social sciences ( spss ) version 13.0 for windows . all data were expressed as the mean  sd . the mann - whitney u and  tests were used for the statistical analysis of the data among all the groups . serum ast , alt , bil , bun , cr , and cpk were measured in the groups of 24 hours postpartum rats with bmods ( table 1 ) . there were significantly ( p < 0.05 ) increased levels of ast , alt , tbil , bun , cr , and cpk in the s+c , s+c+d2.5 , and s+c+d5.0 groups in comparison to the sham group , indicating impaired liver and kidney functions in the postpartum rats with bmods . there were no statistically significant differences ( p > 0.05 ) between the s+c and s+c+d2.5 groups , the s+c and s+c+5.0 groups , and the s+c+d2.5 and s+c+5.0 groups , suggesting that dex administration does not prevent liver and kidney damage in postpartum rats with bmods . abs , including the potential of hydrogen ( ph ) , partial pressure of carbon dioxide in arterial blood ( paco2 ) , partial pressure of oxygen in arterial blood ( pao2 ) , and base excess ( be ) , was measured in postpartum rats with bmods ( table 2 ) . there were significant differences ( p < 0.05 ) between the sham , s+c , and s+c+d2.5/5.0 in the levels of paco2 , pao2 , and be , indicating impaired pulmonary function in postpartum rats with bmods . there was no significant difference ( p > 0.05 ) between s+c and s+c+d2.5 or between s+c and s+c+d5.0 , suggesting that dex administration does not improve abs in postpartum rats with bmods . the mrna expression of ifn- and il-4 in the lung tissue of the s+c group was significantly ( p < 0.05 ) higher than in that of the sham group , indicating that an inflammatory response was elicited in postpartum rats with bmods . the ifn- , il-4 , and ifn-/il-4 mrna ratios were significantly lower in s+c+d2.5 and s+c+d5.0 than in s+c , indicating reduced ifn- and il-4 release upon dex administration during postpartum bmods . there were no statistically significant differences ( p > 0.05 ) in ifn- , il-4 , and ifn-/il-4 mrna expressions between s+c+d2.5 and s+c+d5.0 ( table 3 ) . in comparison to the sham group ( figure 1(a ) ) , lung sections from the s+c group ( figure 1(b ) ) showed acute injury ; the interstitium was expanded by edema and inflammatory infiltrates that were composed of neutrophils , lymphocytes , and histiocytes . the iqa and ait were significantly higher in the s+c group compared to the sham group ( p < 0.05 ) . the s+c+d2.5 and s+c+d5.0 groups showed less severe injury as compared to the s+c group , with significantly lower iqa and ait values ( p < 0.05 ) ( figure 1(c ) ) . no significant differences were detected between the s+c+d2.5 and s+c+d5.0 groups ( table 4 ) . in addition to treatment for sedation and antianxiety , dex has been administered to hypertensive patients during surgery , suggesting a relaxing effect on peripheral vessels . 2ar is distributed not only in the central and peripheral nervous system but also in multiple organ systems , where it exerts its effects on different physiological and pathological processes . for example , the clinical use of dex has become popular in neurosurgery and heart surgery under extracorporeal circulation anesthesia [ 19 , 20 ] . a small number of animal models are available for studying the pathogenesis of bmods , but treatments have been largely unsuccessful , especially in patients with postpartum bmods . it is difficult to study bmods in human subjects because there are many factors involved in the pathogenesis and because there are a wide range of clinical presentations . therefore , the development of a successful animal model is a priority . in the present study , we established a bmods model in postpartum rats . this animal model not only mimics postpartum bleeding - induced shock , but it also mimics reperfusion injury and endotoxicity . the majority of animal models for mods are created by the external administration of endotoxin to induce hypotension . due to the wide range of individual sensitivities to endotoxin , many animals showed either a response too mild to induce hypotension or a response too strong , resulting in death of the animal . the level of hypotension and therefore the degree of injury are difficult to keep constant across groups . in the present study , hypotension the time of clamping of the superior mesenteric artery was kept equal across the groups . together with constant hypotension in rats , our animal model provides a reliable and constant level of damage across all groups for the study of bmods . furthermore , clamping of the superior mesenteric artery induced multiple organ dysfunction syndrome , and it did not induce inflammatory cytokine release simply due to uncontrolled hemorrhagic shock ; inflammatory cytokine release simply due to uncontrolled hemorrhagic shock differs from the response observed in patients undergoing postpartum hypotensive shock . free radicals , calcium overload , and increased leukocytes play important roles in the process of ischemia - reperfusion injury . however , vasoactive peptides , regulatory peptides , inflammatory mediators , damaged cells , and metabolism also play important roles in the shock process . the results in present study showed that dex administration decreased inflammatory cytokine release and damage in the lung in our current model of bmods - induced reperfusion injury . the results showed that dex may prevent organ damage through the inhibition of inflammation and free radical release from leukocytes . the specific mechanism of action of dex in the bmods model needs further research . according to the diagnosis criteria of mods , damage of two or more organs must occur at the same time or sequentially within 24 hours of induction by pathogenic factors . liver , kidney , and lung dysfunctions were evident in the s+c group in the present study ( tables 1 and 2 ) . however , there were no statistically significant differences between the s+c and s+c+d2.5 groups , s+c and s+c+5.0 groups , and s+c+d2.5 and s+c+5.0 groups , suggesting that dex administration did not prevent liver and kidney damage in postpartum rats with bmods . several variables may explain these results , including that the time of dex administration was too short , the specimen collection was too early ( 24 hours ) , or the dose of dex administration was not suitable for use . at later time points of bmods , biochemical markers may be more obviously altered , and increases in inflammatory cytokine release may be more apparent . therefore , dex administration may more clearly reduce biochemical markers and inflammatory cytokines at later time points . there have been several hypotheses regarding the mechanism of mods ( figure 2 ) , including ischemia reperfusion , inflammation , intestinal bacteria , toxin shifts , two strikes double preexcitation syndrome , and stress genes . regardless , the effect of dex on inhibiting cytokine release was confirmed in this study . cd4 + t helper cells are divided into th1 and th2 subsets based on the cytokines they secrete . cytokines play an important role in lymphocyte development , maturation , differentiation , and activation . th1 cells mainly secrete interleukin-2 ( il-2 ) , ifn- , and tumor necrosis factor- ( tnf- ) . th2 cells secrete il-4 , il-5 , il-6 , il-9 , il-10 , and il-13 and are responsible for b lymphocyte proliferation , antibody production , immune tolerance , and humoral immunity [ 24 , 25 ] . therefore ifn- and il-4 are the best respective markers for th1 and th2 cells , and they were chosen to evaluate the changes in immune function in postpartum rats with bmods in the present study . other reports have demonstrated that dex inhibits cytokine release in rats following endotoxin administration . in mice , dex administration led to a decrease in the total number of lung inflammatory cells , a reduction in the concentration of macrophage inflammatory protein-2 ( mip-2 ) and interleukin- ( il- ) , and a decrease in the ratio of dry / wet tissue in the lung . to date , the mechanism underlying the role of dex in the reduction of cytokine secretion is still a matter of debate . one group reported that dex administration led to a reduced inflammatory response during the treatment of spinal cord injury , confirming the anti - inflammatory effects of dex . another group reported that dex protected nerve tissue from reperfusion - induced injury after -erm brain ischemia via reduced levels of tnf- and decreased numbers of degenerative neurons in the hippocampus and dentate gyrus . our findings in the present study showed that dex had strong anti - inflammatory effects on postpartum rats with bmods . as shown in the s+c+d2.5 and s+c+d5.0 groups , dex administration significantly reduced ifn- and il-4 . because both ifn- and il-4 represent humoral and cellular immunity further , a decrease in the ifn-/il-4 ratio suggested that dex suppressed cellular immunity more than humoral immunity . lower malondialdehyde ( mda ) and nitric oxide ( no ) levels and higher superoxide dismutase ( sod ) and catalase ( cat ) were observed in the hippocampus during reperfusion - induced injury in the ischemic rat brain after dex administration . dex inhibited lipid peroxidation of the cell membrane in ischemia reperfusion models [ 3133 ] . further studies are required to address this issue in our model . decreased immune function ( both cellular and humoral ) may induce septic shock . however , dex administration did not lead to septic shock in our bmods model , and this was confirmed by a report that dex administration in early - stage sepsis patients decreased the mortality rate . clinically , dex administration in combination with ketamine reduced mechanical ventilation - induced injury and inflammation in the lungs of endotoxemic rats . in an animal model for spinal cord injury , the administration of dex decreased edema and hemorrhage in gray matter without changing the number of neurons . in the present study , dex administration reduced inflammatory infiltration and edema in the lung , although no significant improvements were observed in abs or liver and kidney function . this finding may provide a basis for additional management options for patients with bmods . in current practice , bmods patients are treated with mechanical approaches to prevent lung injury , including reducing the tidal volume of mechanical ventilation and positive pressure ventilation at the end of breath . however , several studies have explored the combination of dex and ketamine . in summary , the present study demonstrated that dex administration reduced ifn- and il-4 release and decreased lung injury during postpartum bmods . it is possible that dex administration decreased inflammatory cytokine production in bmods by inhibiting inflammation and free radical release by leukocytes independent of the dex dose .
dexmedetomidine ( dex ) is an 2-adrenergic agonist . 
 it decreases the levels of norepinephrine release , resulting in a reduction of postsynaptic adrenergic activity . in the present study , 
 the effects of dex on postpartum bleeding - induced multiple organ dysfunction syndrome ( bmods ) were studied in rats in which bmods was induced by the combination of hypotension and clamping of the superior mesenteric artery . 
 we evaluated the role of dexmedetomidine ( dex ) in cytokine release during postpartum bmods in rats . in summary 
 , the present study demonstrated that dex administration reduced ifn - r and il-4 release and decreased lung injury during postpartum bmods . 
 it is possible that dex administration decreased inflammatory cytokine production in bmods by inhibiting inflammation and free radical release by leukocytes independent of the dex dose .