Sevoflurane prevents vulnerable plaque disruption in apolipoprotein E-knockout mice by increasing collagen deposition and inhibiting inflammation.

BACKGROUND: Sevoflurane may reduce the occurrence of major adverse cardiovascular events (MACCEs) in surgical patients, although the mechanisms are poorly understood. We hypothesised that sevoflurane stabilises atherosclerotic plaques by inhibiting inflammation and enhancing prolyl-4-hydroxylase α1 (P4Hα1), the rate-limiting subunit for the P4H enzyme essential for collagen synthesis. METHODS: We established a vulnerable arterial plaque model in apolipoprotein E-knockout mice (ApoE-/-) fed a high-fat diet that underwent daily restraint/noise stress, with/without a single prior exposure to sevoflurane for 6 h (1-3%; n=30 per group). In vitro, smooth muscle cells (SMCs) were incubated with tumour necrosis factor-alpha in the presence/absence of sevoflurane. Immunohistochemistry, immunoblots, and mRNA concentrations were used to quantify the effect of sevoflurane on plaque formation, expression of inflammatory cytokines, P4Hα1, and collagen subtypes in atherosclerotic plaques or isolated SMCs. RESULTS: In ApoE-/- mice, inhalation of sevoflurane 1-3% for 6 h reduced the aortic plaque size by 8-29% in a dose-dependent manner, compared with control mice that underwent restraint stress alone (P<0.05); this was associated with reduced macrophage infiltration and lower lipid concentrations in plaques. Sevoflurane reduced gene transcription and protein expression levels of pro-inflammatory cytokines (≥69-75%; P<0.05) and matrix metalloproteinases (≥39-65%; P<0.05) at both gene transcription and protein levels, compared with controls. Sevoflurane dose dependently increased Types I and III collagen deposition through enhanced protein expression of P4Hα1, both in vivo and in vitro (0.7-3.3-fold change; P<0.05). CONCLUSIONS: Sevoflurane dose dependently promotes plaque stabilisation and decreases the incidence of plaque disruption in ApoE-/- mice by increasing collagen deposition and inhibiting inflammation. These mechanisms may contribute to sevoflurane reducing MACCE.

Improvement of Water and Nitrogen Use Efficiencies by Alternative Cropping Systems Based on a Model Approach.

The conventional double cropping system of winter wheat and summer maize (WW-SUM) in the North China Plain (NCP) consumes a large amount of water and chemical fertilizer, threatening the sustainable development of agriculture in this region. This study was based on a three-year field experiment of different cropping systems (2H1Y-two harvests in one year; 3H2Y-three harvests in two years; and 1H1Y-one harvest in one year). The 2H1Y system had three irrigation-fertilization practices (FP-farmer's practice; RI-reduced input; and WQ-Wuqiao pattern in Wuqiao County, Hebei Province). A soil-crop system model (WHCNS-soil water heat carbon nitrogen simulator) was used to quantify the effects of different cropping systems on water and nitrogen use efficiencies (WUE and NUE, respectively), and to explore the trade-offs between crop yields and environmental impacts. The results showed that annual yield, water consumption, and the WUE of 2H1Y were higher than those of the 3H2Y and 1H1Y systems. However, local precipitation during the period of crop growth could only meet 65%, 76%, and 91% of total water consumption for the 2H1Y, 3H2Y and 1H1Y systems, respectively. Nearly 65% of irrigation water (groundwater) was used in the period of wheat growth that contributed to almost 40% of the annual yield. Among the three patterns of the 2H1Y system, the order of the WUE was 2H1Y_RI > 2H1Y_WQ > 2H1Y_FP. Compared to 2H1Y_FP, the total fertilizer N application rates in 2H1Y_WQ, 2H1Y_RI, and 3H2Y were reduced by 25%, 65%, and 74%, respectively. The 3H2Y system had the highest NUE of 34.3 kg kg-1, 54% greater than the 2H1Y_FP system (22.2 kg kg-1). Moreover, the 3H2Y system obviously reduced nitrate leaching and gaseous N loss when compared with the other two systems. The order of total N loss of different cropping systems was 2H1Y (261 kg N ha-1) > 1H1Y (78 kg N ha-1) > 3H2Y (70 kg N ha-1). Considering the agronomic and environmental effects as well as economic benefits, the 3H2Y cropping system with optimal irrigation and fertilization would be a promising cropping system in the NCP that could achieve the balance between crop yield and the sustainable use of groundwater and N fertilizer.

E3 ligase RNF99 negatively regulates TLR-mediated inflammatory immune response via K48-linked ubiquitination of TAB2.

Innate immunity is the first line to defend against pathogenic microorganisms, and Toll-like receptor (TLR)-mediated inflammatory responses are an essential component of innate immunity. However, the regulatory mechanisms of TLRs in innate immunity remain unperfected. We found that the expression of E3 ligase Ring finger protein 99 (RNF99) decreased significantly in peripheral blood monocytes from patients infected with Gram negative bacteria (G-) and macrophages stimulated by TLRs ligands, indicating the role of RNF99. We also demonstrated for the first time, the protective role of RNF99 against LPS-induced septic shock and dextran sodium sulfate (DSS)-induced colitis using RNF99 knockout mice (RNF99-/-) and bone marrow-transplanted mice. In vitro experiments revealed that RNF99 deficiency significantly promoted TLR-mediated inflammatory cytokine expression and activated the NF-κB and MAPK pathways in macrophages. Mechanistically, in both macrophages and HEK293 cell line with TLR4 stably transfection, RNF99 interacted with and degraded TAK1-binding protein (TAB) 2, a regulatory protein of the kinase TAK1, via the lysine (K)48-linked ubiquitin-proteasomal pathway on lysine 611 of TAB2, which further regulated the TLR-mediated inflammatory response. Overall, these findings indicated the physiological significance of RNF99 in macrophages in regulating TLR-mediated inflammatory reactions. It provided new insight into TLRs signal transduction, and offered a novel approach for preventing bacterial infections, endotoxin shock, and other inflammatory ills.

Corrigendum: Propofol Protects Myocardium From Ischemia/Reperfusion Injury by Inhibiting Ferroptosis Through the AKT/p53 Signaling Pathway.

[This corrects the article DOI: 10.3389/fphar.2022.841410.].

Propofol Protects Myocardium From Ischemia/Reperfusion Injury by Inhibiting Ferroptosis Through the AKT/p53 Signaling Pathway.

The molecular mechanism underlying the protective role of propofol against myocardial ischemia/reperfusion (I/R) injury remains poorly understood. Previous studies have shown that ferroptosis is an imperative pathological process in myocardial I/R injury. We hypothesized that propofol prevents myocardial I/R injury by inhibiting ferroptosis via the AKT/p53 signaling pathway. The ferroptosis-inducing agent erastin (E) and AKT inhibitor MK2206 (MK) were used to investigate the role of propofol in myocardial I/R injury. H9C2 cells treated without any reagents, erastin for 24 h, propofol for 1 h before adding erastin were assigned as the control (C), E, and E + P group, respectively. Cell viability, reactive oxygen species (ROS), and the expression of antioxidant enzymes, including ferritin heavy chain 1 (FTH1), cysteine/glutamate transporter (XCT), and glutathione peroxidase 4 (GPX4) in H9C2 cells. Rat hearts from the I/R + P or I/R groups were treated with or without propofol for 20 min before stopping perfusion for 30 min and reperfusion for 60 min. Rat hearts from the I/R + P + MK or I/R + MK groups were treated with or without propofol for 20 min, with a 10-min treatment of MK2206 before stopping perfusion. Myocardial histopathology, mitochondrial structure, iron levels, and antioxidant enzymes expression were assessed. Our results demonstrated that erastin increased H9C2 cell mortality and reduced the expression of antioxidant enzymes. I/R, which reduced the expression of antioxidant enzymes and increased iron or p53 (p < 0.05), boosted myocardium pathological and mitochondrion damage. Propofol inhibited these changes; however, the effects of propofol on I/R injury were antagonized by MK (p < 0.05). In addition, AKT siRNA inhibited the propofol-induced expression of antioxidant enzymes (p < 0.05). Our findings confirm that propofol protects myocardium from I/R injury by inhibiting ferroptosis via the AKT/p53 signal pathway.

Propofol Inhibits Ischemia/Reperfusion-Induced Cardiotoxicity Through the Protein Kinase C/Nuclear Factor Erythroid 2-Related Factor Pathway.

Both hydrogen peroxide (H2O2, H) and ischemia/reperfusion (I/R) can damage cardiomyocytes, which was inhibited by propofol (P). The present research was designed to examine whether propofol can reduce myocardial I/R injury by activating protein kinase C (PKC)/nuclear factor erythroid-2-related factor 2 (NRF2) pathway in H9C2 cells and rat Langendorff models. H9C2 cells were disposed of no reagents (C), H2O2 for 24 h (H), propofol for 1 h before H2O2 (H+P), and chelerythrine (CHE, PKC inhibitor) for 1 h before propofol and H2O2 (H+P+CHE). N = 3. The PKC gene of H9C2 was knocked down by siRNA and overexpressed by phorbol 12-myristate 13-acetate (PMA, PKC agonist). The cell viability and the expressions of PKC, NRF2, or heme oxygenase-1(HO-1) were evaluated. Propofol significantly reduced H9C2 cell mortality induced by H2O2, and significantly increased NRF2 nuclear location and HO-1 expression, which were restrained by siRNA knockout of PKC and promoted by PMA. Rat hearts were treated with KrebsHenseleit solution for 120 min (C), with (I/R+P) or without (I/R) propofol for 20 min before stopping perfusion for 30 min and reperfusion for 60 min, and CHE for 10 min before treated with propofol. N = 6. The levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and creatine kinase-MB (CK-MB) in perfusion fluid and antioxidant enzymes in the myocardium were assessed. I/R, which increased LDH and CK-MB expression and reduced SOD expression, boosted the pathological damage and infarcts of the myocardium after reperfusion. However, propofol restrained all these effects, an activity that was antagonized by CHE. The results suggest that propofol pretreatment protects against I/R injury by activating of PKC/NRF2 pathway.

EMAP-II downregulation contributes to the beneficial effects of rapamycin after vascular injury.

AIMS: Neointima formation after vascular injury is strongly associated with inflammation. Rapamycin inhibits human neointima formation and reduces expression of the proinflammatory cytokine endothelial-monocyte activating peptide II (EMAP-II) in vitro. Here we investigated the interplay between EMAP-II and rapamycin after vascular injury in vivo. METHODS AND RESULTS: In a mouse model of vascular injury, mice were either not treated, given everolimus, a rapamycin derivate, or subjected to simultaneous challenge with everolimus and EMAP-II. EMAP-II expression was measured in coronary artery smooth muscle cells (CASMC) and monocytic cells in vitro and in patients after percutaneous coronary intervention (PCI). After vascular injury, rapamycin reduced neointima formation and adventitial thickening. Immunohistochemistry revealed reduced EMAP-II protein expression and suppressed recruitment of inflammatory cells. Simultaneous challenge with EMAP-II counteracted these effects of rapamycin. Expression of EMAP-II and its inhibition by rapamycin was confirmed in CASMC and monocytic cells. In patients, EMAP-II upregulation was confined to PCI of distal coronary artery segments and profoundly suppressed by oral rapamycin treatment. CONCLUSION: These data suggest important yet unrecognized roles of EMAP-II and adventitial inflammation in neointima formation: Through inhibition of EMAP-II, rapamycin reduces the recruitment of inflammatory cells to the adventitia and supports an early and bland healing.

Oxidative stress promotes ventilator-induced lung injury through activating NLRP3 inflammasome and TRPM2 channel.

Ventilator has been widely used for life support, but ventilator-induced lung injury (VILI) is still a major problem. Oxidative stress has been considered as a key contributor for VILI, but the specific mechanism remains unclear. The expression of NLRP3 inflammasome in cells and inflammatory factors in the supernatant were measured. Mitochondrial ROS and TRPM2 channel currents were investigated using flow cytometry and Patch-clamp technique, respectively. TRPM2-/- and NLRP3-/- mice were used for animal experiments. Lung tissues were stained by HE and the wet-dry ratio, bronchoalveolar lavage fluid (BALF) protein, MPO (marrow peroxidase), NLRP3 inflammasome were also investigated. Knockdown of NLRP3 or Caspase-1 or treatments with SS-31 or YVAD inhibited the expression of the NLRP3 inflammasome, and reduced IL-1ß and IL-18 levels in cell supernatant. These treatments suppressed the production of ROS and lowered the TRPM2 channel currents, but Rotenone exerted an opposite effect. High-tidal volume ventilation significantly increased the levels of IL-1ß, IL-18, NLRP3 inflammasome, wet-dry ratio of lung, MPO and BALF protein. However, these parameters were down-regulated in TRPM2-/- and NLRP3-/- mice. These parameters were suppressed in TRPM2-/- and NLRP3-/- mice indicate that oxidative stress might promote VILI through activating NLRP3 inflammasome and TRPM2 channel.

Protective effect of oxytocin on LPS-induced acute lung injury in mice.

Oxytocin (OT), a neurohypophyseal hormone synthesized in the paraventricular and supraoptic nuclei of the hypothalamus, has been reported to have an anti- inflammatory effect. However, its role in acute lung injury (ALI) has never been investigated. The aim of this study was to explore the therapeutic effects and potential mechanism action of OT on lipopolysaccharide (LPS)-induced ALI. Mice were treated with OT 30 min before the intraperitoneal injection of LPS. After 2 h, the effects of OT on lung histopathological changes, lung wet/dry (W/D) ratio, myeloperoxidase (MPO) activity, levels of inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), and expression of inflammation proteins were detected. The results showed that OT significantly reduced LPS-induced pathological injury, W/D ratio, MPO activity, and the levels of interleukin (IL)-1ß, IL-18 and IL-6. Further, OT also inhibited LPS-induced Toll-like receptor 4 expression and NLR family pyrin domain containing 3 inflammasome activation. OT receptor antagonist (L-368,899) was given 90 min before injecting OT to further demonstrate the role of OT in LPS-induced ALI. The results showed OT could not alleviate the aforementioned inflammatory reactions after administering L-368,899. In conclusion, the present results indicated that OT could reduce inflammatory responses of LPS-induced ALI.

Propofol attenuates myocardial ischemia reperfusion injury partly through inhibition of resident cardiac mast cell activation.

Cardiac mast cell activation is involved in the process of myocardial ischemia reperfusion (I/R) injury and exacerbates myocardial infarction. Propofol, an anesthetic with antioxidant property, can reduce myocardial infarct size in I/R injury. The present study was designed to investigate whether propofol can attenuate myocardial I/R injury by inhibiting resident cardiac mast cell activation by a Langendorff model. Thirty rats were randomly assigned to 5 groups (n=6 per group): control group and four test groups (I/R, I/R+compound 48/80, I/R+propofol, I/R+compound 48/80+propofol). Cultured RBL-2H3 cells were pretreated with propofol and subjected to mast cell degranulator compound48/80 (C48/80).Microscopically, degradation of myofibrillar and degranulation of mast cells were studied using hematoxylin-eosin toluidine blue staining techniques. After the effluent was assayed for tryptase, LDH, CK-MB and cTnI, myocardial tissue was evaluated for cytokine levels and infarct area. Heart subjected to I/R showed significantly increased expression of cytokines (TNF-α and IL-6), LDH, CK-MB and cTnI. In addition, the I/R-induced heart also showed greater histopathological injury and a larger infarction zone, following increased mast cell degranulation with concomitant rise in tryptase. Mast cell degranulation by C48/80 further aggravated I/R injury. However, all of these effects were suppressed by propofol pretreatment, which also abrogated C48/80-mediated exacerbation of I/R injury. Also, propofol attenuated the C48/80-evoked tryptase and histamine release in RBL-2H3 cells. It is concluded that pretreatment of propofol confers protection against I/R injury partly by inhibiting resident cardiac mast cell activation.

Dexmedetomidine reduces ventilator-induced lung injury (VILI) by inhibiting Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway.

Mechanical ventilation (MV) may lead to ventilator-induced lung injury (VILI). Previous research has shown that dexmedetomidine attenuates pulmonary inflammation caused by MV, but the underlying mechanisms remain unclear. Our study aims to test whether dexmedetomidine has a protective effect against VILI and to explore the possible molecular mechanisms using the rat model. Thirty adult male Wistar rats weighing 200-250 g were randomly assigned to 5 groups (n = 6): control, low tidal volume MV (LMV), high tidal volume (HVT) MV (HMV), HVT MV + dexmedetomidine (DEX), HVT MV + dexmedetomidine + yohimbine (DEX+Y). Rats were euthanized after being ventilated for 4 hours. Pathological changes, lung wet/dry (W/D) weight ratio, lung myeloperoxidase (MPO) activity, levels of inflammatory cytokines (i.e., interleukin [IL]-1ß, tumor necrosis factor alpha [TNF-α], and IL-6) in the bronchoalveolar lavage fluid (BALF) and lung tissues, expression of Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB, and activation of NF-κB in lung tissues were measured. Compared with HMV, DEX group showed fewer pathological changes, lower W/D ratios and decreased MPO activity of the lung tissues and lower concentrations of the inflammatory cytokines in the BALF and lung tissues. Dexmedetomidine significantly inhibited the expression of TLR4 and NF-κB and activation of NF-κB. Yohimbine partly alleviated the effects of dexmedetomidine. Dexmedetomidine reduced the inflammatory response to HVT-MV and had a protective effect against VILI, with the inhibition of the TLR4/NF-κB signaling pathway, at least partly via α2-adrenoceptors.

Endothelial-monocyte-activating polypeptide II induces migration of endothelial progenitor cells via the chemokine receptor CXCR3.

OBJECTIVE: Recruitment of endothelial progenitor cells to the sites of ischemia has recently been suggested as a mechanism of tissue repair. Here we address the hypothesis that the hypoxia-inducible full-length endothelial-monocyte-activating polypeptide II (EMAP II) provides a mechanism to recruit late outgrowth highly proliferating endothelial progenitor cells (EPCs). MATERIALS AND METHODS: We tested in a transwell migration assay EMAP II for its ability to induce migration of EPCs. Furthermore, we measured changes in cellular calcium levels in EPC to assess the ability of EMAP II to induce intracellular signaling. Finally, we employed neutralizing antibodies and binding competition studies in order to identify the receptor mediating these activities of EMAP II in EPCs. RESULTS: EMAP II elicits dose-dependent migration and intracellular calcium mobilization in EPCs. Functional blocking and binding studies with radiolabeled interferon-gamma-induced protein (IP-10) indicate that EMAP II employs the CXCR3 receptor for these activities in EPCs. Indeed, EMAP II-induced migration of EPCs can be abolished by prior treatment of cells with anti-CXCR3 antibodies or with IP-10. CONCLUSIONS: These data suggests a novel function for EMAP II and a hitherto undescribed role of the CXCR3 chemokine receptor in EPC recruitment.

The protective effect of dopamine on ventilator-induced lung injury via the inhibition of NLRP3 inflammasome.

Dopamine (DA), a neurotransmitter, was previously shown to have anti-inflammatory effects. However, its role in ventilator-induced lung injury (VILI) has not been explicitly demonstrated. This study aimed to investigate the therapeutic efficacy and molecular mechanisms of dopamine in VILI. Rats were treated with dopamine during mechanical ventilation. Afterwards, the influence of dopamine on histological changes, pulmonary edema, the lung wet/dry (W/D) ratio, myeloperoxidase (MPO) activity, polymorphonuclear(PMN)counts, inflammatory cytokine levels, and NLRP3 inflammasome protein expression were examined. Our results showed that dopamine significantly attenuated lung tissue injury, the lung W/D ratio, MPO activity and neutrophil infiltration. Moreover, it inhibited inflammatory cytokine levels in the Bronchoalveolar lavage fluid (BAL). In addition, dopamine significantly inhibited ventilation-induced NLRP3 activation. Our experimental findings demonstrate that dopamine exerted protective effects in VILI by alleviating the inflammatory response through inhibition of NLRP3 signaling pathways. The present study indicated that dopamine could be a potential effective therapeutic strategy for the treatment of VILI.

Propofol reduced myocardial contraction of vertebrates partly by mediating the cyclic AMP-dependent protein kinase phosphorylation pathway.

Propofol inhibits myocardial contraction in a dose dependent manner. The present study is designed to examine the effect of propofol on PKA mediated myocardial contraction in the absence of adrenoreceptor agonist. The contraction of isolated rat heart was measured in the presence or absence of PKA inhibitor H89 or propofol, using a pressure transducer. The levels of cAMP and PKA kinase activity were detected by ELISA. The mRNA and total protein or phosphorylation level of PKA and downstream proteins were tested in the presence or absence of PKA inhibitor H89 or propofol, using RT-PCR, QPCR and western blotting. The phosphorylation level of PKA was examined thoroughly using immunofluorescence and PKA activity non-radioactive detection kit. Propofol induced a dose-dependent negative contractile response on the rat heart. The inhibitory effect of high concentration propofol (50µM) with 45% decease of control could be partly reversed by the PKA inhibitor H89 (10µM) and the depressant effect of propofol decreased from 45% to 10%. PKA kinase activity was inhibited by propofol in a dose-dependent manner. Propofol also induced a decrease in phosphorylation of PKA, which was also inhibited by H89, but did not alter the production of cAMP and the mRNA levels of PKA. The downstream proteins of PKA, PLN and RyR2 were phosphorylated to a lesser extent with propofol or H89 than control. These results demonstrated that propofol induced a negative myocardial contractile response partly by mediating the PKA phosphorylation pathway.

A monoclonal rat anti-mouse EMAP II antibody that functionally neutralizes pro- and mature-EMAP II in vitro.

EMAP II is an endothelial cell and monocyte activating proinflammatory cytokine, which has been demonstrated to induce endothelial cell apoptosis. In order to analyze its role in disease models linked to inflammation and endothelial cell death, we aimed to develop a neutralizing antibody against mouse EMAP II. Therefore, we generated rat monoclonal anti-mouse EMAP II antibodies by immunization with recombinant full length, mouse pro-EMAP II protein. We could identify by ELISA, hybridoma clones from fusion with mouse myeloma SP2/0 cells which produced antibodies recognizing both full length and mature EMAP II. We further characterized one antibody, M7/1 and demonstrated its ability to detect both EMAP II forms in Western blotting and to neutralize EMAP II directed migration of human peripheral blood monocytes as well as EMAP II induced apoptosis of tumor and endothelial cells. We conclude that this antibody can be useful to both target and analyze murine disease models, in which EMAP II may be involved.

Identification of a human B-cell/myeloid common progenitor by the absence of CXCR4.

CXCR4 is a chemokine receptor required for hematopoietic stem cell engraftment and B-cell development. This study found that a small fraction of primitive CD34(+)/CD19(+) B-cell progenitors do not express CXCR4. These CD34(+)/CD19(+)/CXCR4(-) cells were also remarkable for the relative lack of primitive myeloid or lymphoid surface markers. When placed in B-lymphocyte culture conditions these cells matured to express CXCR4 and other surface antigens characteristic of B cells. Surprisingly, when placed in a myeloid culture environment, the CXCR4(-) B-cell progenitors could differentiate into granulocyte, macrophage, and erythroid cells at a high frequency. These data define a novel B-cell/myeloid common progenitor (termed the BMP) and imply a less restrictive pathway of myeloid versus lymphoid development than previously postulated.

Mechanisms and implications of phosphoinositide 3-kinase delta in promoting neutrophil trafficking into inflamed tissue.

The phosphoinositide 3-kinase (PI3K) catalytic subunit p110 delta is expressed in neutrophils and is thought to play a role in their accumulation at sites of inflammation by contributing to chemoattractant-directed migration. We report here that p110 delta is present in endothelial cells and participates in neutrophil trafficking by modulating the proadhesive state of these cells in response to tumor necrosis factor alpha (TNF alpha). Specifically, administration of the selective inhibitor of PI3K delta, IC87114, to animals reduced neutrophil tethering to and increased rolling velocities on cytokine-activated microvessels in a manner similar to that observed in mice deficient in p110 delta. These results were confirmed in vitro as inhibition of this isoform in endothelium, but not neutrophils, diminished cell attachment in flow. A role for PI3K delta in TNF alpha-induced signaling is demonstrated by a reduction in Akt-phosphorylation and phosphatidylinositol-dependent kinase 1 (PDK1) enzyme activity upon treatment of this cell type with IC87114. p110 delta expressed in neutrophils also contributes to trafficking as demonstrated by the impaired movement of these cells across inflamed venules in animals in which this catalytic subunit was blocked or genetically deleted, results corroborated in transwell migration assays. Thus, PI3K delta may be a reasonable therapeutic target in specific inflammatory conditions as blockade of its activity reduces neutrophil influx into tissues by diminishing their attachment to and migration across vascular endothelium.