Kindlin-2 Mediates Lipopolysaccharide-Induced Acute Lung Injury Partially via Pyroptosis in Mice.

Acute lung injury (ALI) is characteristic of the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of pro-inflammatory leukocytes, and intractable hypoxemia, contributing to high mortality. Kindlin-2 is involved in the process of tumor- and wound healing-associated inflammation. However, the effects of kindlin-2 on lipopolysaccharide (LPS)-induced ALI and its mechanisms remain unknown. In this study, we found that the concentration of kindlin-2 was elevated in the lungs of ALI mice. The specific deletion of kindlin-2 by kindlin-2 siRNA attenuated the severity of lung injury, which was demonstrated by the reduced number of pro-inflammatory cells in bronchoalveolar lavage fluid and lung wet/dry weight ratio, and ameliorated pathologic changes in the lungs of ALI mice. Furthermore, kindlin-2 siRNA decreased the mRNA levels of pro-inflammatory factors (IL-1ß, IL-6, and TNF-α) and the protein levels of pyroptosis-related proteins. In vitro studies confirmed that LPS + ATP promoted the expressions of pro-inflammatory factors and pyroptosis-related proteins, which was prevented by kindlin-2 siRNA pretreatment in endothelial cells (ECs). In conclusion, inhibition of kindlin-2 developes protective effects against LPS-induced ALI and the cytotoxicity of ECs, which may depend on blocking pyroptosis.

Activation of TREM-1 induces endoplasmic reticulum stress through IRE-1α/XBP-1s pathway in murine macrophages.

Increasing evidence suggests that endoplasmic reticulum (ER) stress activates several pro-inflammatory signaling pathways in many diseases, including acute lung injury (ALI). We have reported that blocking triggering receptor expressed on myeloid cells 1 (TREM-1) protects against ALI by suppressing pulmonary inflammation in mice with ALI induced by lipopolysaccharides (LPS). However, the molecular mechanism underlying the TREM-1-induced pro-inflammatory microenvironment in macrophages remains unclearly. Herein, we aimed to determine whether TREM-1 regulates the inflammatory responses induced by LPS associated with ER stress activation. We found that the activation of TREM-1 by a monoclonal agonist antibody (anti-TREM-1) increased the mRNA and protein levels of IL-1ß, TNF-α, and IL-6 in primary macrophages. Treatment of the anti-TREM-1 antibody increased the expression of ER stress markers (ATF6, PERK, IRE-1α, and XBP-1s) in primary macrophages. While pretreatment with 4-PBA, an inhibitor of ER stress, significantly inhibited the expression of ER stress markers and pro-inflammatory cytokines and reduced LDH release. Furthermore, inhibiting the activity of the IRE-1α/XBP-1s pathway by STF-083010 significantly mitigated the increased levels of IL-1ß, TNF-α, and IL-6 in macrophages treated by the anti-TREM-1 antibody. XBP-1 silencing attenuated pro-inflammatory microenvironment evoked by activation of TREM-1. Besides, we found that blockade of TREM-1 with LR12 ameliorated ER stress induced by LPS in vitro and in vivo. In conclusion, we conclude that TREM-1 activation induces ER stress through the IRE-1α/XBP-1s pathway in macrophages, contributing to the pro-inflammatory microenvironment.

[Application of ultrasound-guided selective nerve branch blockage in lumbar spinal nerve posterior branch syndrome].

OBJECTIVE: To investigate the efficacy and safety of ultrasound-guided selective nerve branch blockage in the treatment of lumbar spinal nerve posterior branch syndrome. METHODS: A total of 40 patients with lumbar spinal nerve posterior branch syndrome treated by Pain Clinic from May 2017 to December 2018 were selected. According to the method used in locating site for nerve blockage, the patients were divided into ultrasound-guided group and anatomical positioning group, with 20 cases in each group. In anatomical positioning group, there were 7 males and 13 females, aged (63.42±7.71) years old, weighted (63.65±10.72) kg, numerical rating scale (NRS) was (6.61±1.52) scores, course of disease was (16.55±4.68) months. Pain sites:4 cases at L2,3, 8 cases at L3,4, 11 cases at L4,5, and 11 cases at L5S1. In ultrasound-guided group, there were 10 males and 10 females, aged (59.58±10.21) years old, weighted (60.61±13.81) kg, NRS was(6.84±2.43) scores, and course of disease was(13.70±5.98) months. Pain sites:6 cases at L2,3, 6 cases at L3,4, 9 cases at L4,5, and 13 cases at L5S1. Ultrasound-guided group used ultrasound-guided selective posteromedial branch and posterolateral branch nerve blockage, and the anatomical positioning group used anatomical localization method to block the posteromedial branch and posterolateral branch of lumbar spinal nerve. Each nerve branch was injected 3 ml of 0.125% ropivacaine. The number of treatment required and prone position time of each treatment were recorded, and the NRS scores of patients at the time points of immediately after the end of the treatment, the first week, the second week, the first month and the third month were evaluated. And adverse events such as local anesthetic allergy and poisoning, local puncture infection, total spinal anesthesia, dizziness, drowsiness, nausea, vomiting and other adverse reactions were observed. RESULTS: There were no statistically significant differences in gender, age, weight, NRS, course of disease and pain segment distribution between two groups (P>0.05). The number of treatment required in anatomical positioning group was significantly higher than that in ultrasound-guided group (P<0.000 1). During each treatment, the time in the prone position of the patients in anatomical positioning group was significantly lower than that in ultrasound guided group (P< 0.000 1). NRS scores immediately after the end of treatment, 1 week, 2 weeks, 1 month and 3 months, anatomical positioning group were 2.98 ±0.25, 3.04 ±0.38, 3.37 ±0.47, 3.42 ±0.85, 3.50 ±0.43, respectively, 2.94 ±0.31, 3.00 ±0.29, 3.21 ±0.68, 3.16 ± 0.94, 3.17±0.53 in ultrasound-guided group, and there was significant difference at 1 month and 3 months between two groups(P< 0.05). There were no adverse events such as local anesthetic allergy and poisoning, local puncture infection, and total spinal anesthesia, and no adverse reactions such as lethargy, nausea, and vomiting occurred in two groups. There were 6 cases of dizziness in anatomical positioning group and 12 cases in ultrasound guided group. The difference between two groups was statistically significant(P<0.05). CONCLUSION: Comparedwith anatomicalpositioning, ultrasound-guided selective nerve branch block for the treatment of posterior branch of the lumbar spinal cord syndrome can reduce the number of treatments and maintain a longer therapeutic effect, but it is also necessary to pay attention to the time of each treatment to avoid dizziness and other adverse reactions.