Clinical features and mortality-related factors of extensive burns among young adults: the Kunshan disaster experience.

BACKGROUND: The aim of the study was to identify the clinical features and the factors associated with burn induced mortality among young adults after exposure to indoor explosion and fire. METHODS: This is an observational study which included burn patients who were admitted to eighteen ICUs after a fire disaster. Epidemiologic and clinical characteristics, as well as therapy were recorded. The primary outcome was 90-day mortality. The mortality-related factors were also analyzed. RESULTS: There were 167 burn patients enrolled in the study, the median age was 38 years, 62 (37.1%) patients died within 90 days. Seventy-one percent of patients had a burn size ≥90% TBSA, and 73.7% of patients had a full-thickness burn area above 50% TBSA. The survivors had lower Baux scores, and received earlier escharectomy and autologous skin grafts. The 50% mortality rates (LA50s) for burn size and full-thickness burn area were 95.8% and 88.6% TBSA, respectively. The multivariate analysis showed that full-thickness burn area over 50% TBSA and residual burned surface area (RBSA)/TBSA at 28 days were strong predictors of mortality among burn patients (odds ratio 2.55; 95% CI, 1.01 to 6.44, P=0.047; odds ratio 1.07; 95% CI, 1.04 to 1.09, P<0.001). The ROC curve-based cut-off values of RBSA/TBSA at 28 days for predicting 90-day mortality were 62.5%. CONCLUSIONS: Burn size and full-thickness burn area were the main risk factors for poor outcome in patients with extensive burns. Earlier escharectomy and autologous skin grafts may improve outcomes.

[Effects of high glucose induced primary cardiomyocytes injury on necroptosis and the related mechanism].

OBJECTIVE: To observe whether necroptosis was happened in high glucose (HG) - induced primary cardiomyocytes injury and to investigate the likely mechanism. METHODS: The primary cultured cardiomyocytes were divided into 4 groups (n=9): control group (the cardiomyocytes were incubated with 5.5 mmol/L glucose for 48 h), HG group (the cardiomyocytes were incubated with 30 mmol/L glucose for 48 h), HG + necrostatin-1 (Nec-1) group (the cardiomyocytes was co-incubated with necroptosis inhibitor Nec-1 at 100 µmol/L and HG for 48 h) and hypertonic pressure group (HPG, the cardiomyocytes was co-incubated with 5.5 mmol/L glucose and 24.5 mmol/L mannitol for 48 h). Cell viability was measured by MTT method, reactive oxygen species (ROS) generation was measured by DHE staining. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) were tested by ELISA method. The mRNA and protein expressions of necroptosis related genes receptor interacting serine/threonine protein kinase 1 (RIP1), RIP3, mixed lineage kinase domain-like protein (MLKL) were tested by quantitative real-time PCR and Western blot. RESULTS: The results showed HG intervention decreased cardiomyocytes viability, increased ROS generation, up-regulated the levels of TNF-α, IL-6 and IL-1ß, increased RIP1, RIP3, MLKL expressions at mRNA and protein levels. Nec-1 treatment attenuated HG-induced increased cardiomyocytes viability, reduced ROS generation, down-regulated the levels of TNF-α, IL-6 and IL-1ß, decreased RIP1, RIP3, MLKL expressions at mRNA and protein levels. CONCLUSION: Necroptosis was happened in high glucose-induced primary cardiomyocytes injury. Inhibition of necroptosis can reduce high glucose-induced cardiomyocytes damage, may be related to inhibition of oxidative stress and depression of inflammative factors releasing.

[Role of mitochondrial permeability transition pore in mediating the effect of endomorphin-1 postconditioning against myocardial ischemia-reperfusion injury in rats].

OBJECTIVE: To investigate the role of mitochondrial permeability transition pore (MPTP) opening in mediating the effect of endomorphine-1 postconditioning to alleviate myocardial ischemia-reperfusion (IR) injury in rats. METHODS: Forty-five male SD rats were randomized equally for sham operation, myocardial IR injury, endomorphin-1 postconditioning, atractyloside (a MPTP opener) postconditioning, or endomorphin-1 + atractyloside postconditioning. The hemodynamic param-eters of the rats were monitored in real time via carotid artery cannulation to the left ventricle. After reperfusion, plasma samples were collected for biochemical analyses. The size of myocardial infarct area was detected using Evans blue and TTC double staining, and the myocardial expressions of apoptosis-related proteins Bax, Bcl-2 and cleaved caspase-3 were analyzed using Western blotting. RESULTS: Myocardial IR injury resulted in significantly decreased heart rate and blood pressure in the rats (P<0.05). Compared with those in IR group, the rats with endomorphin-1 postconditioning showed significantly increased heart rate and blood pressure (P<0.05), lowered contents or activities of LDH, CK-MB, cTnI, IL-6, TNF-α, Cyt-C and MDA in the plasma (P<0.05), increased plasma SOD activity (P<0.05), reduced size of myocardial infarction, decreased myocardial expression of Bax and cleaved caspase-3 protein (P<0.05), and increased myocardial expression of Bcl-2 protein (P<0.05). All these changes induced by endomorphin-1 were obviously reversed by atractyloside postconditioning (P<0.05). CONCLUSION: Endomorphin-1 postconditioning protects against myocardial IR injury in rats probably by inhibiting the opening of MPTP and reducing cardiac myocyte apoptosis via down-regulating cleaved caspase-3 expression.

[Role of autophagy in fasudil-induced Rho kinase inhibition for protection against myocardial ischemia-reperfusion injury in rats].

OBJECTIVE: To investigate the changes of autophagy in ischemic myocardium of rats treated with fasudil for inhibiting Rho kinase. METHODS: The hearts isolated from male Sprague-Dawley rats were subjected to 30 min of occlusion of the left anterior descending artery followed by 120 min of reperfusion with or without treatment with fasudil or fasudil+Wort. The left ventricular hemodynamics were continuously recorded, and the coronary effluent was collected during the reperfusion to determine lactate dehydrogenase (LDH) levels. The mRNA expressions of autophagy-related genes Atg5 and Beclin1 and apoptosis-related genes bax and bcl-2 were detected by RT-PCR, and the protein expression of caspase-3 was detected by Western blotting. RESULTS: Compared with I/R group, fasudil significantly improved the left ventricular developed pressure, maximal rise/fall rate of left ventricular pressure and rate pressure product, reduced LDH release during reperfusion, increased Atg5 and Beclin1 mRNA expression and the ratio of Bcl-2/Bax, and lowered caspase 3 protein expression. The autophagy inhibitor Wort significantly attenuated the effect of fasudil in the rat hearts. CONCLUSION: Fasudil treatment for inhibiting Rho kinase promoted autophagy in ex vivo rat heart to protect against myocardial ischima-reperfusion injury possibly by reducing apoptosis of the cardiac myocytes.

[Effects of low-concentrations alcohol consumption on the expression of mitofusin-2 in myocardial injury of diabetic rats].

OBJECTIVE: To observe the effects of low-concentrations of alcohol consumption on the expression of mitofusin-2 (mfn2) in myocardial injury of diabetic rats. METHODS: Diabetic rat model was simulated by intraperitoneal injection of 55 mg/kg streptozotocin (STZ) and divided into control group, diabetes mellitus(DM) and diabetes+ethanol (DM+EtOH) groups (n=6). When diabetic model was suc-ceed, daily consumption of 2.5% ethanol was used in ethanol+diabetic group after one week, then changed to 5% ethanol continued until 8 weeks. Eight weeks after the modeling, heart perfusion ex vivo. The ventricular hemodynamic parameters were recorded, the serum levels of lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) were determined by automatic biochemistry analyzer, the mfn2 protein ex-pression of left anterior myocardium was evaluated by Western blot and immunohistochemistry. RESULTS: Compared with control group, the left ventricular development pressure (LVDP), heart rate (HR) and rate pressure product (RPP) were decreased, however, left ventricular and diastolic pressure (LVEDP) and LDH, AST release were increased, the expression of mfn2 protein was decreased in DM group. Compared with DM group, LVDP, HR and RPP and the expression of mfn2 protein were increased, LVEDP and LDH, AST were decreased in DM+E-tOH group. CONCLUSIONS: The expression of mfn2 protein was decreased in myocardial injury of diabetic rats, low-concentrations of alcohol consumption increased the expression of mfn2. It suggests that mfn2 may be participated in the cardiac protective role of low-concentrations al-cohol intervene in diabetic rat.

[Effects of activation of ALDH2 by ethanol on the expression of JNK in kidney of diabetic rats].

OBJECTIVE: To observe the effect of activation of aldehyde dehydrogenase 2 (ALDH2) by ethanol on the expression of c-Jun N-terminal kinase (JNK) in the kidney of diabetic rats. METHODS: Eightheen healthy male SD rats were randomly divided into 3 groups (n = 6): normal control group, diabetes group and ethanol + diabetes group. After 8 weeks, 24 h urine samples from rats were collected to detect urinary protein content. The kidney was isolated and the ratio of kidney weight/body weight (index of kidney weight) was detected. The levels of fasting blood glucose, glycosylated hemoglobin serum urea nitrogen and serum creatinine were measured. Morphological changes of renal tissue were observed by optical microscope. The protein expressions of ALDH2 and JNK in renal tissue were detected by Western blot. RESULTS: Compared with the normal control rats, the levels of fasting blood glucose, glycosylated hemoglobin, serum urea nitrogen, serum creatinine and the index of kidney weight were increased markedly in diabetic rats. The expression of ALDH2 protein was decreased, while p-JNK, JNK protein expressions and the ratio of p-JNK/JNK were increased. The morphological observation was shown that the amount of glomerular mesangial matrix were increased, basement membrane were thickened and capillary lumen were narrowed. However,in ethanol + diabetes group, renal function was improved and the damage of renal structure was attenuated. The expression of ALDH2 protein was increased, while p-JNK, JNK and the ratio of p-JNK/JNK were decreased. CONCLUSION: Enhanced ALDH2 expression can protect kidney in diabetic rats, which may be relevant with inhibitting the activity of JNK pathway.

Remote ischemic postconditioning protects the heart by upregulating ALDH2 expression levels through the PI3K/Akt signaling pathway.

Remote ischemic postconditioning (RIPostC) has been demonstrated to protect the myocardium against ischemia/reperfusion (I/R) injury; however, the mediator and underlying mechanisms remain to be elucidated. It has been confirmed that aldehyde dehydrogenase 2 (ALDH2) is involved in the remote ischemic preconditioning pathway, but whether it is involved in RIPostC remains unknown. The aim of the present study was to determine whether increased ALDH2 expression levels were involved in the cardioprotective effect evoked by RIPostC via the phosphatidylinositol­3­kinase (PI3K)/Akt signaling pathway. Male Sprague Dawley rats (n=48) were randomly allocated into the following four groups: Sham group, I/R group, RIPostC group, and RIPostC plus wortmannin group (RIPostC+Wort). With the exception of the Sham group, the anesthetized rats underwent 45 min of coronary artery occlusion followed by 180 min of reperfusion to mimic an I/R injury model. Hemodynamic parameters, including the mean arterial pressure and heart rate, were recorded, the infarct size was determined and the plasma lactate dehydrogenase (LDH) content and creatine kinase (CK) activity levels were measured. The expression levels of Bcl­2 and Bax at the mRNA level and ALDH2, Akt, phospho­Akt (p­Akt), caspase­3 and cleaved caspase­3 at the protein level in the left anterior myocardium were assessed. In the RIPostC group, the infarct size was reduced versus that of the I/R group. The plasma LDH content and CK activity levels were also reduced. The expression levels of ALDH2 protein were elevated, accompanied with increases in the levels of Bcl­2/Bax and p­Akt/Akt and a reduction in the levels of cleaved caspase­3. When the PI3K inhibitor wortmannin was administered at reperfusion, the p­Akt/Akt ratio was markedly reduced and associated with a reduction in the ALDH2 and Bcl­2/Bax levels, and the cleaved caspase­3 expression levels were elevated. In conclusion, ALDH2 may be an important mediator in the cardioprotection of RIPostC through the PI3K/Akt­dependent signaling pathway.

[The changes of inducible nitric oxide synthase activity and apoptosis-related gene expression in endotoxemia-induced rat diaphragm].

OBJECTIVE: To study the changes of inducible nitric oxide synthase (iNOS) activity and apoptosis-related genes Bcl-2, Bax and caspase-3 mRNA expressions in endotoxemia-induced rat diaphragm injury and analyze the related apoptosis mechanism. METHODS: Thirty-two male SD rats were randomly divided into 4 groups (n = 8): control group (saline 0.5 ml ip), endotoxin 24 h, 48 h and 96 h group (endotoxin 12 mg/kg ip, animals were killed either 24, 48 or 96 h after injections). Body weight were measured, the ratio between diaphragm weight and body weight, activities of constitutive nitric oxide syntheses (cNOS), iNOS and succinate dehydrogenase (SDH) were also measured. The expressions of Bcl-2, Bax and caspase-3 mRNA were detected by RT-PCR analysis. RESULTS: Endotoxin induced significant reductions in diaphragm mass in endotoxin 96 h group (P < 0.05). Endotoxin increased diaphragm cNOS or iNOS activities, and they were significantly higher in endotoxin 96 h group than those in endotoxin 24 h and 48 h groups, diaphragm SDH activity was reduced, and it was lower in endotoxin 96 h group than that in endotoxin 24 h and 48 h groups (P < 0.01). Endotoxin significantly increased Bax and caspase-3 mRNA expressions, and they were higher in endotoxin 48 h and 96 h groups than those in endotoxin 24 h group (P < 0.01). Endotoxin significantly reduced Bcl-2 mRNA expression and the ratio of Bcl-2/Bax, and they were lower in endotoxin 48 h and 96 h groups than those in endotoxin 24 h group (P < 0.01). CONCLUSION: iNOS is activated in endotoxemia-induced rat diaphragm injury. It damages mitochondria, upregulates Bax expression and downregulates Bcl-2 expression, then induces caspase-3 related apoptotic pathway. These changes may cause diaphragm injury and atrophy.

Changes in cardiac mitochondrial aldehyde dehydrogenase 2 activity in relation to oxidative stress and inflammatory injury in diabetic rats.

The aim of the present study was to determine the changes in mitochondrial aldehyde dehydrogenase 2 (ALDH2) activity in relation to oxidative stress and inflammatory injury in different stages of diabetes mellitus (DM) in rats and to investigate the related mechanisms. DM in Sprague-Dawley (SD) rats was induced by a single intraperitoneal injection of 55 mg/kg streptozotocin (STZ). The rats were randomly allocated into a control group, as well as into DM4w, DM8w and DM12w groups containing DM rats 4, 8 and 12 weeks after DM induction, respectively. Ventricular hemodynamic parameters were recorded; fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) levels were determined using an automatic biochemistry analyzer; plasma interleukin (IL)-1, IL-4 and cardiac 4-hydroxynon-2-enal (4-HNE) levels were determined using enzyme-linked immunosorbent assay (ELISA), and cardiac ALDH2 activity was measured. The mRNA expression levels of Bax and Bcl-2 of the left anterior myocardium were detected by reverse transcriptase­polymerase chain reaction (RT-PCR). FBG and HbA1c levels were increased in the DM groups compared to the control group. FBG levels were not significantly different among the DM4w, DM8w and DM12w groups, while HbA1c levels were increased with the progression of diabetes. The left ventricular developed pressure (LVDP), heart rate (HR) and rate-pressure product (RPP) were decreased, plasma IL-1 levels were increased, while IL-4 levels were decreased in the DM groups compared to the control group. Additionally, cardiac 4-HNE levels were increased, and ALDH2 activity was decreased in the DM groups compared to the control group. Bax mRNA levels were increased, Bcl-2 mRNA levels were decreased, and Bcl-2/Bax mRNA ratios were decreased in the DM groups compared to the control group. Moreover, LVDP, HR, RPP, IL-4, ALDH2 activity and Bcl-2/Bax mRNA ratios were further reduced, while 4-HNE and IL-1 levels were increased with the progression of diabetes. In conclusion, our results indicated that cardiac ALDH2 activity was further decreased with the progression of diabetes, which might be related to the increase of oxidative stress, inflammatory injury and the occurrence of apoptosis.

Activation of ALDH2 with ethanol attenuates diabetes induced myocardial injury in rats.

This study assessed changes in myocardial ALDH2 expression in the diabetic rat, in particular the diabetic rat pretreated with ALDH2 activator ethanol (EtOH). The rats were divided into six groups: control, EtOH control, diabetic rat at 4th week (DM4W), 8th week (DM8W), 12th week (DM12W) and EtOH+DM8W groups. Compared with control group, fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) levels were increased in DM groups. HbA1c level in DM12W group was higher than in DM4W group, HbA1c level in EtOH+DM8W group was lower than in DM8W group. Compared with control group, there were no changes of LVDP, HR and ±dp/dtmax in DM4W group, but there were decreased in DM8W and DM12W groups, and increased in the EtOH+DM8W group. In DM groups, SOD activity, ALDH2 mRNA and protein levels were reduced, MDA content was increased compared with control group; which decreased further as diabetes progressed. Compared with DM8W group, SOD and ALDH2 in EtOH+DM8W group was increased, MDA was decreased. Our results indicated with the development of diabetes, myocardial ALDH2 expression was further decreased accompanying decreased ventricular function. However, activation of ALDH2 can decrease diabetes induced myocardial injury. ALDH2 may be one key endogenous cardiac protective factor in diabetic individuals.

Changes in the expression of cardiac mitofusin-2 in different stages of diabetes in rats.

The aim of this study was to investigate the role of mitofusin-2 (Mfn2) in different stages of diabetes in rats and to analyze the related mechanism(s). A diabetic model in SD rats was induced by a single intraperitoneal injection of 55 mg/kg streptozoticin (STZ). The hearts were isolated from diabetes mellitus (DM) rats at the fourth week (DM4W), eighth week (DM8W) and twelfth week (DM12W) and fasting blood glucose (FBG) levels and the ratio of heart weight to body weight (HW/BW) were measured. Malondialdehyde (MDA) content, superoxide dismutase (SOD) and caspase 3 activities were measured. The expression of Mfn2 of the left anterior myocardium at the mRNA level was detected using RT­PCR. In contrast to the normal group, in the DM4W, DM8W and DM12W groups, there was a significant increase in the FBG levels, but no difference among the DM4W, DM8W and DM12W groups. The HW/BW ratio as well as the MDA content were increased, while SOD activity was reduced. Caspase­3 activity was increased, while the expression of Mfn-2 mRNA levels was reduced. In addition, with the development of diabetic cardiomyopathy, the contents of MDA and caspase 3 were increased, whereas SOD activity and Mfn-2 mRNA levels were further reduced. In conclusion, our results indicated that with the development of diabetes, the expression of cardiac Mfn2 has showed a decrease, which may be associated with the decrease of antioxidant ability and progression of apoptosis.

[Effect of ALDH2 activation against myocardial ischemia/reperfusion injury in diabetic rat].

OBJECTIVE: To observe the role of activation of aldehyde dehydrogenase 2 (ALDH2) on myocardial ischemia/reperfusion (I/ R) injury in diabetic rats. METHODS: Diabetic rat model was simulated by intraperitoneal injection 55 mg/kg streptozotocin (STZ) and divided into diabetes and ethanol + diabetes groups (n = 8). After 8 weeks, myocardial ischemia/reperfusion model was mimicked in vitro. The ventricular dynamical parameters and lactate dehydrogenase (LDH) content in coronary flow were determined. The fasting blood glucose and glycosylated hemoglobin (HbA1c) level were determined by automatic biochemistry analyzer. The ALDH2 mRNA and protein expressions of left anterior myocardium were evaluated by RT-PCR and Western blot. RESULTS: In contrast to I/R in normal rat, in diabetic rat, left ventricular development pressure (LVDP), maximal rise/fall rate of left ventricular pressure (+/- dp/dtmax) and left ventricular work (RPP) were decreased, left ventricular end diastolic pressure (LVEDP) and LDH release were increased, and ALDH2 mRNA and protein expressions were decreased; compared with I/R in diabetic rat, ALDH2 agonist ethanol significantly promoted the recovery of LVDP, +/- dp/dtmax, RPP, reduced HbA1c level, LVEDP and LDH released, ALDH2 mRNA and protein expressions were increased. CONCLUSION: In diabetic rat, the expression of ALDH2 was decreased when heart was subjected to I/R. Enhanced mitochondrial ALDH2 expression in diabetic rat could play cardiac protective role.

[Anti-apoptotic role of mitochondrial aldehyde dehydrogenase 2 in myocardial ischemia/reperfusion injury in diabetic rats].

OBJECTIVE: To evaluate the anti-apoptotic effect of aldehyde dehydrogenase 2 (ALDH2) on myocardial ischemia/reperfusion (I/R) injury in diabetic rats. METHODS: Normal male SD rats were divided into normal, diabetes and ethanol (the agonist of ALDH2) + diabetes groups. In the latter two groups, diabetes was induced by an intraperitoneal injection of 55 mg/kg STZ. Four weeks after the modeling, myocardial I/R was mimicked ex vivo, and lactate dehydrogenase (LDH) content in the coronary flow was determined. The activities of caspase-3 and ALDH2 were evaluated, and the expressions of Bcl-2 and Bax mRNA in the left anterior myocardium were detected using RT-PCR. RESULTS: In diabetic group, LDH release and caspase-3 activity were increased, while ALDH2 activity and Bcl-2/Bax mRNA expression were decreased as compared to those in normal control group. Compared with the diabetic group, ALDH2 agonist ethanol significantly reduced LDH release and caspase-3 activity, increased ALDH2 activity and Bcl-2/Bax mRNA expression. CONCLUSION: In diabetic rats, enhanced ALDH2 expression can offer mycardial protection possibly in relation to suppress cell apoptosis.

[Activation of mitochondrial aldehyde dehydrogenase 2 and inhibition of mitochondrial permeability transition pore involved in cardioprotection of ethanol postconditioning].

OBJECTIVE: To investigate whether activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) and inhibition of mitochondrial permeability transition pore (mitoPTP) were involved in the cardioprotection of ethanol postconditioning in isolated rat heart. METHODS: Hearts isolated from male Sprague-Dawley rats were perfused on a langendorff apparatus and subjected to 30 min of regional ischemia (occlusion of left anterior descending artery) followed by 120 min of reperfusion. The ventricular hemodynamic parameters and lactate dehydrogenase (LDH) release during reperfusion were measured. Infarct size was measured by TTC staining method and the expression of ALDH2 at mRNA level of left anterior myocardium was detected by RT-PCR. RESULT: In contrast to ischemia and reperfusion, ethanol postconditioning improved the recovery of left ventricular developed pressure, maximal rise/fall rate of left ventricular pressure during reperfusion, reduced LDH release and infarct size. The expression of ALDH2 mRNA level was increased. Administration of mitoPTP activator atractyloside attenuated the effect of ethanol postconditioning, LDH release and infarct size were increased, and the recovery of hemodynamic parameters was inhibited. The expression of ALDH2 mRNA was decreased. CONCLUSION: Ethanol postconditioning has cardioprotection effect, which may be associated with upregulating mitochondrial ALDH2 mRNA expression and inhibiting the opening of mitochondrial permeability transition pore.

Pharmacokinetic study with N-Ile1-Thr2-63-desulfato-r-hirudin in rabbits by means of bioassay.

AIM: To study the pharmacokinetic (PK) properties in rabbits treated with N-Ile(1)-Thr(2)-63-desulfato-r-hirudin (rH) newly developed in China by means of bioassay in order to provide preclinical experiment basis for its development as a novel anticoagulant agent. METHODS: rH plasma concentration was determined using bioassay based on ex vivo antithrombin activity of rH. Normal rabbits received iv rH 4.0, 2.0 and 1.0 mg/kg or sc rH 2.0 mg/kg, respectively. The rabbits with acute severe renal failure were given iv rH 2.0 mg/kg. RESULTS: The bioassay described in this paper met requirements for study of PK in rabbits. The major PK parameters after iv dosing were as follows: t(1/2beta) 58.4-59 min. V(d) 0.09-0.12 L/kg, CL 0.0035-0.0040 L/(kg.min); AUC were proportional to the doses, t(1/2) and CL did not change significantly with the doses. The sc bioavailability reached 94%. The rabbits suffering from acute severe renal failure presented 11-fold longer t(1/2beta) and 13-fold greater AUC than normal healthy rabbits. CONCLUSION: rH exhibited rapid elimination, distribution was only limited to extracellular space and good absorption from sc site. The excretion of rH by kidneys played a very important role in the elimination of rH. The PK of rH could be described by the two- and one-compartment model after iv and sc dosing, respectively, and followed linear kinetics.