Hongxu Jin

Recombinant human brain natriuretic peptide ameliorates trauma-induced acute lung injury via inhibiting JAK/STAT signaling pathway in rats.

BACKGROUND JAK/STAT signal pathway plays an important role in the inflammation process of acute lung injury (ALI). This study aimed to investigate the correlation between recombinant human brain natriuretic peptide (rhBNP) and the JAK/STAT signaling pathway and to explore the protective mechanism of rhBNP against trauma-induced ALI. METHODS The arterial partial pressure in oxygen, lung wet-dry weight ratios, protein content in bronchoalveolar lavage fluid, the histopathologic of the lung, as well as the protein expressions of STAT1, JAK2, and STAT3 were detected. RESULTS Sprague-Dawley rats were randomly divided into five groups: a control group, a sham-operated group, an ALI group, an ALI + rhBNP group, and an ALI + AG490 group. At 4 hours, 12 hours, 1 day, 3 days, and 7 days after injury, injured lung specimens were harvested. rhBNP pretreatment significantly ameliorated hypoxemia and histopathologic changes and alleviated pulmonary edema in trauma-induced ALI rats. rhBNP pretreatment reduced the phosphorylated protein and total protein level of STAT1. Similarly to JAK-specific inhibitor AG490, rhBNP was shown to significantly inhibit the phosphorylation of JAK2 and STAT3 in rats with trauma-induced ALI. CONCLUSION Our experimental findings indicated that rhBNP can protect rats against trauma-induced ALI and that its underlying mechanism may be related to the inhibition of JAK/STAT signaling pathway activation.

Protective effects of recombinant human brain natriuretic peptide against LPS-Induced acute lung injury in dogs

BACKGROUND Acute lung injury (ALI) is a common component of systemic inflammatory disease without more effective treatments. However, recent studies have demonstrated that the recombinant human brain natriuretic peptide (rhBNP) has anti-inflammatory effects. Therefore, we found that rhBNP could prevent lipopolysaccharide (LPS)-induced acute lung injury in a dog model. METHODS Dogs were injected with LPS and subjected to continuous intravenous infusion (CIV) of saline solution or rhBNP. We detected the protective effects of rhBNP by histological examination and determination of serum cytokine levels and lung myeloperoxidase (MPO) activity and malondialdehyde (MDA) activity. Histological examination indicated marked inflammation, edema and hemorrhage in lung tissue taken 12h after rhBNP treatment compared with tissue from dogs which received saline treatment after LPS injection. LPS injection induced cytokine (IL-6 and TNF-α) secretion and lung MPO and MDA activities, which were also attenuated by rhBNP treatment. RESULTS Inductions of IL-6 and TNF-α were significantly attenuated in the L-rhBNP and the H-rhBNP groups. The ratios of the L-rhBNP group and H-rhBNP group were lower than that in the lung injury group. Furthermore, MPO and MDA activities were significantly lower in the H-rhBNP group compared to those in the LI group. CONCLUSION Our data indicate that rhBNP treatment may exert protective effects and may be associated with adjusting endogenous antioxidant enzymes. Thus, rhBNP may be considered as a therapeutic agent for various clinical conditions involving lung injury by sepsis.

Protective effect of rhBNP on intestinal injury in the canine models of sepsis

Sepsis is the leading cause of death in the intensive care units worldwide. Proinflammatory cytokines such as TNF (tumor necrosis factor)-α and IL (interleukin)-6 mediate the pathogenesis of septic shock characterized by hemodynamic instability and end-stage multi-organ functional failure. Brain natriuretic peptide (BNP) has been used as a diagnostic and prognostic biomarker in the cardiovascular disorders. Most recently, plasma level of BNP has also been used to predict outcomes of critical illnesses including sepsis. We have recently reported that human recombinant BNP (rhBNP) could protect lungs from acute proinflammatory injury in response to LPS-injection. In the current study, using LPS (lipopolysaccharide)-induced canine sepsis models, we further investigated the effect of rhBNP on intestinal injury and its potential mechanisms. We have found that rhBNP (5μg or 10μg/kg weight) could significantly reduce intestinal tissue damage in response to LPS-injection in the dog sepsis models through down-regulating proinflammatory cytokines TNF-α and IL-6 (5-10 fold decrease compared to LPS-injection only group) by a mechanism of suppressing IκB phosphorylation and NF-κB expression. These findings suggest that BNP protect intestinal tissues from endotoxin-induced hyper-inflammatory injury and thus, may be used as therapeutic agents for sepsis.

Cold stress-induced brain injury regulates TRPV1 channels and the PI3K/AKT signaling pathway

Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that interacts with several intracellular proteins in vivo, including calmodulin and Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt). TRPV1 activation has been reported to exert neuroprotective effects. The aim of this study was to examine the impact of cold stress on the mouse brain and the underlying mechanisms of TRPV1 involvement. Adult male C57BL/6 mice were subjected to cold stress (4°C for 8h per day for 2weeks). The behavioral deficits of the mice were then measured using the Morris water maze. Expression levels of brain injury-related proteins and mRNA were measured by western blot, immunofluorescence or RT-PCR analysis. The mice displayed behavioral deficits, inflammation and changes in brain injury markers following cold stress. As expected, upregulated TRPV1 expression levels and changes in PI3K/Akt expression were found. The TRPV1 inhibitor reduced the levels of brain injury-related proteins and inflammation. These data suggest that cold stress can induce brain injury, possibly through TRPV1 activation and the PI3K/Akt signaling pathway. Suppression of inflammation by inhibition of TRPV1 and the PI3K/Akt pathway may be helpful to prevent cold stress-induced brain injury.

Recombinant human brain natriuretic peptide attenuates trauma-/haemorrhagic shock-induced acute lung injury through inhibiting oxidative stress and the NF-κB-dependent inflammatory/MMP-9 pathway

Acute lung injury (ALI) is one of the most serious complications in traumatic patients and is an important part of multiple organ dysfunction syndrome (MODS). Recombinant human brain natriuretic peptide (rhBNP) is a peptide with a wide range of biological activity. In this study, we investigated local changes in oxidative stress and the NF‐κB‐dependent matrix metalloproteinase‐9 (MMP‐9) pathway in rats with trauma/haemorrhagic shock (TH/S)‐induced ALI and evaluated the effects of pretreatment with rhBNP. Forty‐eight rats were randomly divided into four groups: sham operation group, model group, low‐dosage rhBNP group and high‐dosage rhBNP group (n = 12 for each group). Oxidative stress and MPO activity were measured by ELISA kits. MMP‐9 activity was detected by zymography analysis. NF‐κB activity was determined using Western blot assay. With rhBNP pretreatment, TH/S‐induced protein leakage, increased MPO activity, lipid peroxidation and metalloproteinase (MMP)‐9 activity were inhibited. Activation of antioxidative enzymes was reversed. The phosphorylation of NF‐κB and the degradation of its inhibitor IκB were suppressed. The results suggested that the protection mechanism of rhBNP is possibly mediated through upregulation of anti‐oxidative enzymes and inhibition of NF‐κB activation. More studies are needed to further evaluate whether rhBNP is a suitable candidate as an effective inhaling drug to reduce the incidence of TH/S‐induced ALI.

Chitosan oligosaccharide ameliorates acute lung injury induced by blast injury through the DDAH1/ADMA pathway.

Objective To investigate the protective effect of chitosan oligosaccharide (COS) on acute lung injury (ALI) caused by blast injury, and explore possible molecular mechanisms. Methods A mouse model of blast injury-induced ALI was established using a self-made explosive device. Thirty mice were randomly assigned to control, ALI and ALI + COS groups. An eight-channel physiological monitor was used to determine the mouse physiological index. Enzyme linked immunosorbent assay was used to measure serum inflammatory factors. Hematoxylin-eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, immunofluorescence staining, real time-polymerase chain reaction and western blot assay were used to detect inflammatory reactions, oxidative stress and apoptosis. Results Mice were sacrificed 24 hours after successful model induction. Compared with the ALI group, the heart rate, respiration and PCO2 were significantly lower, but the PO2, TCO2 and HCO3- were significantly higher in the ALI + COS group. Compared to ALI alone, COS treatment of ALI caused a significant decrease in the wet/dry lung weight ratio, indicating a reduction in lung edema, inflammatory cell infiltration, levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-4, IL-6 and nuclear factor kappa B mRNA and protein expression were reduced and IL-10 mRNA and protein expression was increased (P < 0.05). COS significantly inhibited reactive oxygen species, MDA5 and IREα mRNA and protein expressions, cell apoptosis and Bax and Caspase-3 mRNA and protein expressions, and significantly increased superoxide dismutase-1 mRNA expression, and Bcl-2 and Caspase-8 mRNA and protein expression (all P<0.05). COS significantly increased dimethylarginine dimethylaminohydrolase 1 (DDAH1) protein expression, and reduced ADMA and p38 protein expression (P< 0.05). Conclusion Blast injury causes inflammation, oxidative stress and apoptosis in the lung tissues of mice. COS has protective effects on blast injury-induced ALI, possibly by promoting DDAH1 expression and inhibiting ADMA and mitogen-activated protein kinase pathways.

Anti-inflammatory effect of tranexamic acid against trauma-hemorrhagic shock-induced acute lung injury in rats

It has been demonstrated that tranexamic acid (TXA), a synthetic derivative of lysine, alleviates lung damage in a trauma-hemorrhagic shock (T/HS) model. Nevertheless, the mechanism of TXA against acute lung injury (ALI) has not deeply elaborated. In this study, we generated a T/HS rat model based on previous research, and TXA (50 mg/kg and 100 mg/kg) was intravenously injected into these rats prior to or post T/HS. The results revealed that the decreased survival rate and impaired lung permeability of the rats caused by T/HS were improved by TXA pretreatment or posttreatment. T/HS-triggered over-generation of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in bronchoalveolar fluid and serum was inhibited by TXA, and the enzymatic activity of myeloperoxidase (MPO) in lung tissues was suppressed by TXA as well. Furthermore, TXA treatment deactivated the poly ADP-ribose polymerase-1 (PARP1)/nuclear factor κB (NF-κB) signaling pathway in the lungs of T/HS rats, as evidenced by increased IκBα expression, and decreased cleaved PARP1, p-p65 (Ser276), p-p65 (Ser529), p-IκBα (ser32/ser36), and intercellular adhesion molecule-1. While the expression level of total p65 did not change after T/HS, its DNA binding activity was strengthened. Both TXA pretreatment and posttreatment suppressed this effect on the DNA binding activity of NF-κB. Taken together, our results reveal that administration of TXA effectively relieves T/HS-induced ALI, at least in part, by attenuating the abnormal pulmonary inflammation.