Lipoxin A4 levels predict site-specific clinical improvements post scaling and root planing and correlate negatively with periodontal pathogens in severe periodontitis.

BACKGROUND: Serving as a stop signal of inflammation, the role of lipoxin A4 (LXA4) in periodontitis remains to be clarified. This study is aimed to examine the changes in LXA4 levels in gingival crevicular fluid (GCF) after scaling and root planing (SRP) and to determine the relationship between LXA4 levels and treatment outcomes and periodontal pathogens in severe periodontitis. METHODS: A total of 74 GCF samples were collected from 21 severe periodontitis participants at the deepest affected sites. These sites were re-sampled at 1, 3, and 6 months after SRP. Besides, GCF samples were also collected from 25 periodontally healthy participants. Clinical parameters including probing depth (PD) and clinical attachment level (CAL) in periodontitis group were recorded. LXA4 levels and periodontal pathogens in the GCF were analyzed by ELISA and PCR, respectively. Correlations between GCF LXA4 levels and treatment effect and periodontal pathogens were assessed. RESULTS: LXA4 levels in GCF significantly increased after SRP (p < 0.05), but remained lower than those observed in healthy individuals (p < 0.05). Sites with lower baseline LXA4 concentrations were more likely to experience greater improvements in PD at 6 months post-SRP (area under the curve [AUC] = 0.792), and the improvements were positively correlated with the increase of LXA4 at these sites post-treatment (p < 0.05). Furthermore, more elevated LXA4 levels were observed in sites that became negative for Prevotella intermedia or Tannerella forsythia after SRP. CONCLUSION: Baseline LXA4 in GCF has the potential to predict the site-specific response of severe periodontal lesions to SRP. The increase of LXA4 levels after treatment was positively correlated with clinical improvements and negatively correlated with the presence of Prevotella intermedia or Tannerella forsythia.

BML-111, the agonist of lipoxin A4, suppresses epithelial-mesenchymal transition and migration of MCF-7 cells via regulating the lipoxygenase pathway.

Introduction: Aberrant epithelial-mesenchymal transition (EMT) and migration frequently occur during tumour progression. BML-111, an analogue of lipoxin A4, has been implicated in inflammation in cancer research. Methods: 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, western blot, Reverse Transcription Polymerase Chain Reaction (RT-PCR), transwell assay, immunofluorescence, and immunohistochemistry were conducted in this study. Results: In vitro experiments revealed that BML-111 inhibited EMT and migration in CoCl2-stimulated MCF-7 cells. These effects were achieved by inhibiting MMP-2 and MMP-9, which are downregulated by 5-lipoxygenase (5-LOX). Moreover, BML-111 inhibited EMT and migration of breast cancer cells in BALB/c nude mice inoculated with MCF-7 cells. Conclusion: Our results suggest that BML-111 may be a potential therapeutic drug for breast cancer and that blocking the 5-LOX pathway could be a possible approach for mining effective drug targets.

The effect of low-dose aspirin on aspirin triggered lipoxin, interleukin 1 beta, and prostaglandin E2 levels in periapical fluid: a double-blind randomized clinical trial.

BACKGROUND: The role of pro-resolving mediators in inflammation is a new concern in research. The effect of low-dose aspirin on production of a special kind of these mediators named aspirin triggered lipoxin (ATL) has been studied on different tissues. This randomized clinical trial evaluated the effect of low-dose aspirin on ATL and pro-inflammatory mediators' level in periapical fluid of necrotic teeth with large lesions. METHODS: Twenty-four patients with necrotic pulp and periapical lesion were randomly assigned to low-dose aspirin and placebo groups. In the first appointment, canals were shaped up to F3 size and #40 K-file and cleaned with 10 milliliters 2.5% sodium hypochlorite and 17% Ethylenediaminetetraacetic acid. Periapical fluid was sampled by a paper cone. The tooth was temporized without any intracanal medication. Tablets were administered for 7 days, then the teeth were re-opened and the sampling were repeated. Interleukin-1 beta (IL-1ß), prostaglandin E2 (PGE2) and ATL were analyzed by enzyme-linked immunosorbent assay. Data were analyzed with paired t-test using SPSS statistical software, version 21 (α = 0.05). RESULTS: A significant reduction in PGE2 and IL-1ß was noted in the aspirin-treated group while an increase in ATL was observed (P < 0.001). There was no significant difference in the mediator scores before and after in the placebo-treated group (P > 0.05). CONCLUSION: Low-dose aspirin can influence the inflammatory process by reducing pro-inflammatory mediators such as PGE2 and IL-1ß, as well as increasing the pro-resolving mediators such as ATL. TRIAL REGISTRATION: IRCT20191211045702N1.

Lipoxin Mimetics and the Resolution of Inflammation.

Inflammation and its timely resolution are critical to ensure effective host defense and appropriate tissue repair after injury and or infection. Chronic, unresolved inflammation typifies many prevalent pathologies. The key mediators that initiate and drive the inflammatory response are well defined and targeted by conventional anti-inflammatory therapeutics. More recently, there is a growing appreciation that specific mediators, including arachidonate-derived lipoxins, are generated in self-limiting inflammatory responses to promote the resolution of inflammation and endogenous repair mechanisms without compromising host defense. We discuss the proresolving biological actions of lipoxins and recent efforts to harness their therapeutic potential through the development of novel, potent lipoxin mimetics generated via efficient, modular stereoselective synthetic pathways. We consider the evidence that lipoxin mimetics may have applications in limiting inflammation and reversing fibrosis and the underlying mechanisms.

Development of synthetic lipoxin-A4 mimetics (sLXms): New avenues in the treatment of cardio-metabolic diseases.

Resolution of inflammation is a complex, dynamic process consisting of several distinct processes, including inhibition of endothelial activation and leukocyte trafficking; promotion of inflammatory cell apoptosis and subsequent non-phlogistic scavenging and degradation; augmentation of pathogen phagocytosis; modulation of stromal cell phenotype coupled to the promotion of tissue regeneration and repair. Among these tightly regulated processes, the clearance and degradation of apoptotic cells without eliciting an inflammatory response is a crucial allostatic mechanism vital to developmental processes, host defence, and the effective resolution of inflammation. These efferocytic and subsequent effero-metabolism processes can be carried out by professional and non-professional phagocytes. Defective removal or inadequate processing of apoptotic cells leads to persistent unresolved inflammation, which may promote insidious pathologies including scarring, fibrosis, and eventual organ failure. In this manuscript, the well-established role of endothelial activation and leukocyte extravasation, as classical vascular targets of the 'inflammation pharmacology', will be briefly reviewed. The main focus of this work is to bring attention to a less explored aspect of the 'resolution pharmacology', aimed at tackling defective efferocytosis and inefficient effero-metabolism, as key targeted mechanisms to prevent or pre-empt vascular complications in cardio-metabolic diseases. Despite the use of gold standard lipid-lowering drugs or glucose-lowering drugs, none of them are able to tackle the so called residual inflammatory risk and/or the metabolic memory. In this review, the development of synthetic mimetics of endogenous mediators of inflammation is highlighted. Such molecules finely tune key components across the whole inflammatory process, amongst various other novel therapeutic paradigms that have emerged over the past decade, including anti-inflammatory therapy. More specifically, FPR2-agonists in general, and Lipoxin analogues in particular, greatly enhance the reprogramming and cross-talk between classical and non-classical innate immune cells, thus inducing both termination of the pro-inflammatory state as well as promoting the subsequent resolving phase, which represent pivotal mechanisms in inflammatory cardio-metabolic diseases.

Prognostic impacts of Lipoxin A4 in patients with acute myocardial infarction: A prospective cohort study.

Lipoxin A4 (LXA4) is one of the specialized pro-resolving lipid mediators proved to suppress the progression of atherosclerosis in vivo, but its clinical impacts in atherosclerotic patients is unclear. In this study, we assessed the prognostic impacts of LXA4 in patients with acute myocardial infarction (AMI). A total of 1569 consecutive AMI patients were prospectively recruited from March 2017 to January 2020. Plasma samples of AMI patients were collected, and LXA4 levels were determined using enzyme-linked immunosorbent assay. The primary outcome was major adverse cardiovascular event (MACE), a composite of all-cause death, recurrent MI, ischemic stroke, or ischemia-driven revascularization. Cox regression was used to assess associations between LXA4 and clinical outcomes. Overall, the median level of LXA4 was 5.637 (3.047-9.014) ng/mL for AMI patients. During a median follow-up of 786 (726-1108) days, high LXA4 (≥ 5.637 ng/mL) was associated with lower risk of MACE (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: 0.60-0.89, P = 0.002), which was sustained in propensity score matching (HR: 0.73, 95% CI: 0.60-0.90, P = 0.004) and inverse probability weighting analysis (HR: 0.74, 95% CI: 0.61-0.90, P = 0.002). Combined with pro-inflammatory biomarker, patients with high levels of LXA4 (≥ 5.637 ng/mL) but low levels of high-sensitivity C-reactive protein (< 5.7 mg/L) acquired the lowest risk of MACE (HR: 0.68, 95% CI: 0.51-0.92, P = 0.012). In sum, high levels of LXA4 were associated with lower risk of recurrent ischemic events for AMI patients, which could serve as new therapeutic target to tackle cardiovascular inflammation.

Specialized Pro-Resolving Mediators Reduce Scarring After Cleft Lip Repair.

Objective: Residual scarring after cleft lip repair surgery remains a challenge for both surgeons and patients and novel therapeutics are critically needed. The objective of this preclinical experimental study was to evaluate the impact of the methyl-ester of pro-resolving lipid mediator lipoxin A4 (LXA4-ME) on scarring in a novel rabbit model of cleft lip repair. Methods: A defect of the lip was surgically created and repaired in eight six-week old New Zealand white rabbits to simulate human cleft lip scars. Rabbits were randomly assigned to topical application of PBS (control) or 1 ug of LXA4-ME (treatment). 42 days post surgery all animals were euthanized. Photographs of the cleft lip area defect and histologic specimens were evaluated. Multiple scar assessment scales were used to compare scarring. Results: Animals treated with LXA4-ME exhibited lower Visual Scar Assessment scores compared to animals treated with PBS. Treatment with LXA4-ME resulted in a significant reduction of inflammatory cell infiltrate and density of collagen fibers. Control animals showed reduced 2D directional variance (orientation) of collagen fibers compared to animals treated with LXA4-ME demonstrating thicker and more parallel collagen fibers, consistent with scar tissue. Conclusions: These data suggest that LXA4-ME limits scarring after cleft lip repair and improves wound healing outcomes in rabbits favoring the resolution of inflammation. Further studies are needed to explore the mechanisms that underlie the positive therapeutic impact of LXA4-ME on scarring to set the stage for future human clinical trials of LXA4-ME for scar prevention or treatment after cleft lip repair.

The Effect and Mechanism of Lipoxin A4 on Neutrophil Function in LPS-Induced Lung Injury.

Excessive inflammatory response caused by infiltration of a large number of neutrophils is one of the important features of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Lipoxin A4 (LXA4) is an important endogenous mediator in the process of inflammation resolution, which has a strong role in promoting inflammation resolution. In this study, we examined the impact of LXA4 on the pulmonary inflammatory response and the neutrophil function in ARDS rats. Our results indicated that exogenous administration of LXA4 could reduce the degree of lung injury in ARDS rats and inhibit the release of pro-inflammatory factors TNF-α and IL-1ß in lung tissue homogenate. However, LXA4 has no lung protective effect on ARDS rats of neutropenia, nor can it inhibit the levels of pro-inflammatory factors TNF-α and IL-1ß in lung tissue homogenate. LXA4 can inhibit the production of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) in peripheral blood neutrophils of ARDS rats. At the same time, LXA4 can promote the phagocytosis of neutrophils in ARDS rats in vitro and can also promote the apoptosis of neutrophils in ARDS rats. In addition, the effect of LXA4 on the function of neutrophils in ARDS rats is mediated by its receptor ALX. LXA4 can inhibit the release of NE and MPO from neutrophils, thereby reducing the production of NETs. In summary, these findings indicate that LXA4 has a protective effect on LPS-induced ARDS rats by affecting the function of neutrophils.

Lipoxins in inflammation.

Lipoxins and ATL appear to be the first recognized members of a new class of endogenous mediator that are anti-inflammatory or serve for the "pro-resolution" of inflammation. PGE2 can and may display anti-inflammatory properties in certain settings, but in most cases, it enhances inflammation in vivo. This is likely the result of numerous receptor isoforms and differential coupled mechanisms for PGE2 and its diverse role in human physiology. Since the integrated response of the host is essential to health and disease, it is important to achieve a more complete understanding of the molecular and cellular events governing the formation and actions of endogenous mediators of resolution that appear to control the magnitude and duration of inflammation. In view of the present body of evidence, it is not surprising that a protective action for inhibition of COX-2 was found in cardiovascular disease. Characterizing useful experimental systems with clinically relevant endpoints will also take a multidisciplinary approach and require a shift in our current thinking about inflammation and the role of lipid mediators.

Lipoxin A4 attenuates the lung ischaemia reperfusion injury in rats after lung transplantation.

BACKGROUND: Lung ischaemia reperfusion injury (LIRI) is the major cause of primary lung dysfunction after lung transplantation. Lipoxin A4 inhibits the oxidative stress and inflammation. This study aimed to evaluate the potential protective effect of lipoxin A4 on LIRI in rats. METHODS: SD (Sprague-Dawley) rats were randomised into the sham, LIRI and LA4 groups. Rats in the sham group received anaesthesia, thoracotomy and intravenous injection of saline, while those in the LIRI or LA4 group received left lung transplantation and intravenous injection of saline or lipoxin A4, respectively. After 24 h of reperfusion, the PaO2/FiO2 (Partial pressure of O2 to fraction inspiratory O2), wet/dry weight ratios and protein levels in lungs were measured to assess the alveolar capillary permeability. The oxidative stress response and inflammation were examined. The histological and apoptosis analyses of lung tissues were performed via HE staining (Haematoxylin-eosin staining) and TUNEL assay, respectively. The effects of lipoxin A4 on the endothelial viability and tube formation of hypoxaemia and reoxygenation-challenged rat pulmonary microvascular endothelium cells were determined. RESULTS: Lipoxin A4 significantly ameliorated the alveolar capillary permeability, reduced the oxidative stress and inflammation in transplanted lungs. The histological injury and apoptosis of lung tissues were also alleviated by lipoxin A4. In vitro lipoxin A4 treatment promoted the endothelial tube formation and improved the endothelial viability. CONCLUSION: Lipoxin A4 protects LIRI after lung transplantation in rats, and its therapeutic effect is associated with the properties of anti-inflammation, anti-oxidation, and endothelium protection.Key messages:Lung transplantation is a treatment approach for the patients with lung disease.LIRI is the major cause of postoperative primary lung dysfunction.Lipoxins A4 exhibits strong anti-inflammatory properties.

Lipoxin A4 Restores Septic Renal Function via Blocking Crosstalk Between Inflammation and Premature Senescence.

Acute kidney injury (AKI) occurs in half of patients with septic shock, resulting in unacceptably high mortality. However, effective preventive treatments are still lacking. We hypothesized that pretreatment with lipoxin A4 (LXA4), known to promote inflammation resolution, may attenuate septic AKI via blocking crosstalk between inflammation and cellular senescence. In this study, rats developed AKI following cecal ligation and puncture (CLP), as evidenced by a dynamic increase in serum creatinine, blood urea nitrogen, urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and pathological injury, accompanied by increased levels of inflammation (IL-6, TNF-α, and HMGB1) and tubular cell senescence. While, on the one hand, inhibition of senescence with rapamycin restored renal function and attenuated septic inflammatory response, on the other hand, LXA4 administration inhibited renal inflammation and tubular epithelial cell senescence after CLP. Ultimately, pretreatment with LXA4 significantly restored renal function and increased the survival rate of rats after CLP. Furthermore, LXA4 inhibited NF-κB-mediated inflammatory response and the p53/p21 senescence pathway in vivo and in vitro. However, the effect was reversed by PPAR-γ siRNA and antagonist. These results indicated that LXA4 exerted its renoprotective effects by blocking the crosstalk between inflammation and premature senescence in a PPAR-γ-dependent manner. Our findings also suggested that premature senescence plays a critical role in septic AKI and that inhibition of the crosstalk between inflammation and premature senescence may represent a new and major mechanism through which LXA4 attenuates septic AKI.

Resolution-Based Therapies: The Potential of Lipoxins to Treat Human Diseases.

Inflammation is an a physiological response instead an essential response of the organism to injury and its adequate resolution is essential to restore homeostasis. However, defective resolution can be the precursor of severe forms of chronic inflammation and fibrosis. Nowadays, it is known that an excessive inflammatory response underlies the most prevalent human pathologies worldwide. Therefore, great biomedical research efforts have been driven toward discovering new strategies to promote the resolution of inflammation with fewer side-effects and more specificity than the available anti-inflammatory treatments. In this line, the use of endogenous specialized pro-resolving mediators (SPMs) has gained a prominent interest. Among the different SPMs described, lipoxins stand out as one of the most studied and their deficiency has been widely associated with a wide range of pathologies. In this review, we examined the current knowledge on the therapeutic potential of lipoxins to treat diseases characterized by a severe inflammatory background affecting main physiological systems, paying special attention to the signaling pathways involved. Altogether, we provide an updated overview of the evidence suggesting that increasing endogenously generated lipoxins may emerge as a new therapeutic approach to prevent and treat many of the most prevalent diseases underpinned by an increased inflammatory response.

Specialized proresolving mediators in infection and lung injury.

Specialized proresolving mediators (SPMs) are endogenous lipid metabolites of long-chain polyunsaturated fatty acids that are involved in promoting the resolution of inflammation. Many disease conditions characterized by excessive inflammation have impaired or altered SPM biosynthesis, which may lead to chronic, unresolved inflammation. Exogenous administration of SPMs in infectious conditions has been shown to be effective at improving infection clearance and survival in preclinical models. SPMs have also shown tremendous promise in the context of inflammatory lung conditions, such as acute respiratory distress syndrome and chronic obstructive pulmonary disease, mostly in preclinical settings. To date, SPMs have not been studied in the context of the novel Coronavirus, severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), however their preclinical efficacy in combatting infections and improving acute respiratory distress suggest they may be a valuable resource in the fight against Coronavirus disease-19 (COVID-19). Overall, while the research on SPMs is still evolving, they may offer a novel therapeutic option for inflammatory conditions.

Obesity-Driven Deficiencies of Specialized Pro-resolving Mediators May Drive Adverse Outcomes During SARS-CoV-2 Infection.

Obesity is a major independent risk factor for increased morbidity and mortality upon infection with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), which is responsible for the current coronavirus disease pandemic (COVID-19). Therefore, there is a critical need to identify underlying metabolic factors associated with obesity that could be contributing toward increased susceptibility to SARS-CoV-2 in this vulnerable population. Here, we focus on the critical role of potent endogenous lipid metabolites known as specialized pro-resolving mediators (SPMs) that are synthesized from polyunsaturated fatty acids. SPMs are generated during the transition of inflammation to resolution and have a vital role in directing damaged tissues to homeostasis; furthermore, SPMs display anti-viral activity in the context of influenza infection without being immunosuppressive. We cover evidence from rodent and human studies to show that obesity, and its co-morbidities, induce a signature of SPM deficiency across immunometabolic tissues. We further discuss how the effects of obesity upon SARS-CoV-2 infection are likely exacerbated with environmental exposures that promote chronic pulmonary inflammation and augment SPM deficits. Finally, we highlight potential approaches to overcome the loss of SPMs using dietary and pharmacological interventions. Collectively, this mini-review underscores the need for mechanistic studies on how SPM deficiencies driven by obesity and environmental exposures may exacerbate the response to SARS-CoV-2.

Neuromodulation, Specialized Proresolving Mediators, and Resolution of Pain.

The current crises in opioid abuse and chronic pain call for the development of nonopioid and nonpharmacological therapeutics for pain relief. Neuromodulation-based approaches, such as spinal cord stimulation, dorsal root ganglion simulation, and nerve stimulation including vagus nerve stimulation, have shown efficacy in achieving pain control in preclinical and clinical studies. However, the mechanisms by which neuromodulation alleviates pain are not fully understood. Accumulating evidence suggests that neuromodulation regulates inflammation and neuroinflammation-a localized inflammation in peripheral nerves, dorsal root ganglia/trigeminal ganglia, and spinal cord/brain-through neuro-immune interactions. Specialized proresolving mediators (SPMs) such as resolvins, protectins, maresins, and lipoxins are lipid molecules produced during the resolution phase of inflammation and exhibit multiple beneficial effects in resolving inflammation in various animal models. Recent studies suggest that SPMs inhibit inflammatory pain, postoperative pain, neuropathic pain, and cancer pain in rodent models via immune, glial, and neuronal modulations. It is noteworthy that sham surgery is sufficient to elevate resolvin levels and may serve as a model of resolution. Interestingly, it has been shown that the vagus nerve produces SPMs and vagus nerve stimulation (VNS) induces SPM production in vitro. In this review, we discuss how neuromodulation such as VNS controls pain via immunomodulation and neuro-immune interactions and highlight possible involvement of SPMs. In particular, we demonstrate that VNS via auricular electroacupuncture effectively attenuates chemotherapy-induced neuropathic pain. Furthermore, auricular stimulation is able to increase resolvin levels in mice. Thus, we propose that neuromodulation may control pain and inflammation/neuroinflammatioin via SPMs. Finally, we discuss key questions that remain unanswered in our understanding of how neuromodulation-based therapies provide short-term and long-term pain relief.

15-Epi-LXA4 and 17-epi-RvD1 restore TLR9-mediated impaired neutrophil phagocytosis and accelerate resolution of lung inflammation.

Timely resolution of bacterial infections critically depends on phagocytosis of invading pathogens by polymorphonuclear neutrophil granulocytes (PMNs), followed by PMN apoptosis and efferocytosis. Here we report that bacterial DNA (CpG DNA) and mitochondrial DNA impair phagocytosis and attenuate phagocytosis-induced apoptosis in human PMNs through Toll-like receptor 9 (TLR9)-mediated release of neutrophil elastase and proteinase 3 and subsequent down-regulation of the complement receptor C5aR. Consistently, CpG DNA delays pulmonary clearance of Escherichia coli in mice and suppresses PMN apoptosis, efferocytosis, and generation of proresolving lipid mediators, thereby prolonging lung inflammation evoked by E. coli Genetic deletion of TLR9 renders mice unresponsive to CpG DNA. We also show that aspirin-triggered 15-epi-lipoxin A4 (15-epi-LXA4) and 17-epi-resolvin D1 (17-epi-RvD1) through the receptor ALX/FPR2 antagonize cues from CpG DNA, preserve C5aR expression, restore impaired phagocytosis, and redirect human PMNs to apoptosis. Treatment of mice with 15-epi-LXA4 or 17-epi-RvD1 at the peak of inflammation accelerates clearance of bacteria, blunts PMN accumulation, and promotes PMN apoptosis and efferocytosis, thereby facilitating resolution of E. coli-evoked lung injury. Collectively, these results uncover a TLR9-mediated endogenous mechanism that impairs PMN phagocytosis and prolongs inflammation, and demonstrate both endogenous and therapeutic potential for 15-epi-LXA4 and 17-epi-RvD1 to restore impaired bacterial clearance and facilitate resolution of acute lung inflammation.

Lipoxin suppresses inflammation via the TLR4/MyD88/NF-κB pathway in periodontal ligament cells.

OBJECTIVE: The objective of the present study was to evaluate the anti-inflammatory effects of lipoxin A4 (LXA4) for the treatment of periodontitis in an in vitro model. METHODS: Human PDLCs were challenged with Escherichia coli (E. coli) lipopolysaccharide (LPS) to evoke an inflammatory response. This was done either in monoculture or in coculture with THP-1, a monocytic cell line. Thereafter, cytokine expression was measured by ELISA, with or without LXA4. In addition, the effects of LXA4 were analyzed on the TLR-MyD88-NF-κB (TMN)-mediated intracellular signal pathway using immunocytochemistry. RESULTS: In response to LPS, the level of the pro-inflammatory cytokine tumor necrosis factor alpha increased, whereas the anti-inflammatory cytokine interleukin-4 decreased significantly (p < .05). These effects were consistently reversed when LPS-challenged PDLCs were also treated with LXA4. The results in the coculture system were comparable to the monoculture. Immunohistochemistry and quantitative assessment confirmed the importance of the TMN signal pathway in these processes. CONCLUSION: These results corroborate earlier findings that PDLCs play an important role in inflammation. Moreover, LXA4 might offer new approaches for the therapeutic treatment of periodontal disease.

Lipoxin A4 ameliorates lipopolysaccharide-induced lung injury through stimulating epithelial proliferation, reducing epithelial cell apoptosis and inhibits epithelial-mesenchymal transition.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is characterized by alveolar epithelial disruption. Lipoxins (LXs), as so-called "braking signals" of inflammation, are the first mediators identified to have dual anti-inflammatory and inflammatory pro-resolving properties. METHODS: In vivo, lipoxinA4 was administrated intraperitoneally with 1 µg/per mouse after intra-tracheal LPS administration (10 mg/kg). Apoptosis, proliferation and epithelial-mesenchymal transition of AT II cells were measured by immunofluorescence. In vitro, primary human alveolar type II cells were used to model the effects of lipoxin A4 upon proliferation, apoptosis and epithelial-mesenchymal transition. RESULTS: In vivo, lipoxin A4 markedly promoted alveolar epithelial type II cells (AT II cells) proliferation, inhibited AT II cells apoptosis, reduced cleaved caspase-3 expression and epithelial-mesenchymal transition, with the outcome of attenuated LPS-induced lung injury. In vitro, lipoxin A4 increased primary human alveolar epithelial type II cells (AT II cells) proliferation and reduced LPS induced AT II cells apoptosis. LipoxinA4 also inhibited epithelial mesenchymal transition in response to TGF-ß1, which was lipoxin receptor dependent. In addition, Smad3 inhibitor (Sis3) and PI3K inhibitor (LY294002) treatment abolished the inhibitory effects of lipoxinA4 on the epithelial mesenchymal transition of primary human AT II cells. Lipoxin A4 significantly downregulated the expressions of p-AKT and p-Smad stimulated by TGF-ß1 in primary human AT II cells. CONCLUSION: LipoxinA4 attenuates lung injury via stimulating epithelial cell proliferation, reducing epithelial cell apoptosis and inhibits epithelial-mesenchymal transition.

Lipoxin A4 reduces hyperoxia-induced lung injury in neonatal rats through PINK1 signaling pathway.

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature infants and is mainly caused by hyperoxia exposure and mechanical ventilation. Alveolar simplification, pulmonary vascular abnormalities and pulmonary inflammation are the main pathological changes in hyperoxic lung injury animals. Lipoxin A4 (LXA4) is an important endogenous lipid that can mediate the regression of inflammation and plays a role in acute lung injury and asthma. The purpose of this study was to evaluate the effects of LXA4 on inflammation and lung function in neonatal rats with hyperoxic lung injury and to explore the mechanism of the PINK1 pathway. After 85% oxygen exposure in newborn rats for 7 days, the BPD model was established. We found that LXA4 could significantly reduce cell and protein infiltration and oxidative stress in rat lungs, improve pulmonary function and alveolar simplification, and promote weight gain. LXA4 inhibited the expression of TNF-α, MCP-1 and IL-1ß in serum and BALF from hyperoxic rats. Moreover, we found that LXA4 could reduce the expression of the PINK1 gene and down-regulate the expression of PINK1, Parkin, BNIP3L/Nix and the autophagic protein LC3B.These protective effects of LXA4 could be partially reversed by addition of BOC-2.Thus, we concluded that LXA4 can alleviate the airway inflammatory response, reduce the severity of lung injury and improve lung function in a hyperoxic rat model of BPD partly through the PINK1 signaling pathway.

LXA4 ameliorates cerebrovascular endothelial dysfunction by reducing acute inflammation after subarachnoid hemorrhage in rats.

Lipoxin A4 (LXA4) has been reported to reduce inflammation in experimental subarachnoid hemorrhage (SAH), but the mechanism remains unclear. In this study, we investigated the role of LXA4 in inflammation-mediated cerebrovascular endothelial dysfunction and the potential mechanism after SAH. SAH was induced by endovascular perforation in male Sprague-Dawley rats, and recombinant LXA4 was injected intracerebroventricularly 1.5 h after the operation. The expression changes in the markers of endothelial dysfunction (endothelial microparticles and nitric oxide) were analyzed by flow cytometry or Nitric Oxide (NO) assay kit. Microflow in the cerebral cortex was assayed by laser speckle contrast imaging. Neutrophil infiltration was observed by a marker of leukocyte activity (myeloperoxidase, MPO) that colocalized with a specific marker of endothelial cells (von Willebrand factor, VWF). The expression of LXA4 and its downstream molecules, formyl peptide receptor 2 (FPR2), extracellular signal-regulated kinase (ERK1/2), nuclear factor-κB (NF-κB), matrix metalloproteinase-9 (MMP9), and the levels of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6), leukocyte adhesion molecule (intercellular adhesion molecule-1, ICAM-1) and MPO were measured either by Western blot or enzyme-linked immunosorbent assay (ELISA). SAH resulted in endothelial dysfunction and a reduction in microflow in the cerebral cortex. The expression of LXA4 was decreased, and the expression of pro-inflammatory factors (NF-κB, MMP9, ICAM-1, MPO) and cytokines (TNF-α, IL-1ß, IL-6) was increased after SAH. The administration of LXA4 significantly ameliorated endothelial dysfunction, recovered microflow, and suppressed the inflammation and infiltration of neutrophils in SAH rats. The underlying mechanism of this outcome may involve the LXA4/FPR2/ERK1/2 pathway. LXA4 might be a promising candidate for acute SAH treatment.