Effects of COVID-19 Status on Hip Fracture Surgical Outcomes: An ACS NSQIP Study.

BACKGROUND: Studies have indicated that patients infected with the SARS-CoV-2 virus fare worse clinically after a traumatic injury, especially those who are older and have other comorbidities. OBJECTIVE: This study aims to understand the effects of Corona Virus Disease 19 (COVID-19) diagnosis on patients undergoing surgery for hip fractures. METHODS: This is a retrospective review of the 2021 American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) Targeted Hip Fracture database for patients who underwent surgery. Two cohorts were formed based on patients' preoperative COVID-19 status, as tested within 14 days prior to the operation. Several clinical factors were compared. RESULTS: The COVID-positive cohort consisted of 184 patients, all of whom had a laboratory-confirmed or clinically suspected SARS-CoV-2 infection, while the COVID-negative cohort consisted of 12,211 patients with no infection. A lower proportion of COVID-positive patients had an emergent operation compared to the COVID-negative cohort (58.70% vs. 73.09%, p < .001). Preoperatively, the COVID-positive cohort showed higher rates of coagulopathy/bleeding disorders (22.83% vs. 14.12%), congestive heart failure (16.30% vs. 9.84%), diabetes mellitus (28.26% vs. 19.24%), and dementia (42.39% vs. 28.07%), with p ≤ .005 for all. Postoperatively, a higher proportion of COVID-positive patients died (9.78% vs. 5.40%) or had pneumonia (8.70% vs. 3.65%), hospital readmission within 30 days (10.87% vs. 6.76%), and pressure sores (8.15% vs. 4.55%), with p ≤ .033 for all. CONCLUSION: The diagnosis of COVID-19 in hip fracture patients was associated with higher rates of postoperative complications, including mortality, when compared to COVID-negative patients, indicating the severity of the viral infection.

Effects of the COVID-19 Pandemic on Colectomy Outcomes for Inflammatory Bowel Disease.

OBJECTIVES: Inflammatory bowel disease (IBD) encompasses Crohn's disease (CD) and ulcerative colitis (UC). These two chronic inflammatory conditions can differ in severity, presentation, and anatomical localization, and can greatly affect quality of life if not managed properly. Given the many healthcare challenges during the coronavirus disease 2019 pandemic, we studied the effects of the pandemic and corresponding changes to medical resources on surgical outcomes for patients with IBD. METHODS: Deidentified data from patients who underwent a colectomy for CD or UC were collected from the National Surgical Quality Improvement Program database of the American College of Surgeons. We analyzed clinical factors and surgical outcomes between 2019 and 2020. RESULTS: Patients with IBD were more likely to have lost >10% of their body mass before the operation in 2020. Operations for patients with UC were significantly shorter in the first year of the pandemic. Patients with CD were less likely to have a urinary tract infection or sepsis postoperatively in 2020, whereas patients with UC were more likely to require a repeat operation. Interestingly, both patient populations were less likely to undergo an emergency operation in 2020 than in 2019. CONCLUSIONS: Colectomy outcomes for patients with CD in 2020 were similar or improved in comparison with those seen in 2019, whereas colectomies for UC saw a statistically but not clinically significant increase in the rate of repeat operations. Overall, these patients seem to have been well managed despite the coronavirus disease 2019 pandemic-induced strain on the healthcare system.

EVALUATION OF COMPONENTS OF THE EXTRACELLULAR PURINERGIC SIGNALING SYSTEM IN HUMAN SEPSIS.

ABSTRACT: Objective: Extracellular purines such as adenosine triphosphate (ATP), uridine triphosphate (UTP), and uridine diphosphate (UDP) and the ATP degradation product adenosine are biologically active signaling molecules, which accumulate at sites of metabolic stress in sepsis. They have potent immunomodulatory effects by binding to and activating P1 or adenosine and P2 receptors on the surface of leukocytes. Here we assessed the levels of extracellular purines, their receptors, metabolic enzymes, and cellular transporters in leukocytes of septic patients. Methods: Peripheral blood mononuclear cells (PBMCs), neutrophils, and plasma were isolated from blood obtained from septic patients and healthy control subjects. Ribonucleic acid was isolated from cells, and mRNA levels for purinergic receptors, enzymes, and transporters were measured. Adenosine triphosphate, UTP, UDP, and adenosine levels were evaluated in plasma. Results: Adenosine triphosphate levels were lower in septic patients than in healthy individuals, and levels of the other purines were comparable between the two groups. Levels of P1 and P2 receptors did not differ between the two patient groups. mRNA levels of ectonucleoside triphosphate diphosphohydrolase (NTPDase) 1 or CD39 increased, whereas those of NTPDase2, 3, and 8 decreased in PBMCs of septic patients when compared with healthy controls. CD73 mRNA was lower in PBMCs of septic than in healthy individuals. Equilibrative nucleoside transporter (ENT) 1 mRNA concentrations were higher and ENT2, 3, and 4 mRNA concentrations were lower in PBMCs of septic subjects when compared with healthy subjects. Concentrative nucleoside transporter (CNT) 1 mRNA levels were higher in PBMCs of septic versus healthy subjects, whereas the mRNA levels of CNT2, 3, and 4 did not differ. We failed to detect differences in mRNA levels of purinergic receptors, enzymes, and transporters in neutrophils of septic versus healthy subjects. Conclusion: Because CD39 degrades ATP to adenosine monophosphate (AMP), the lower ATP levels in septic individuals may be the result of increased CD39 expression. This increased degradation of ATP did not lead to increased adenosine levels, which may be explained by the decreased expression of CD73, which converts AMP to adenosine. Altogether, our results demonstrate differential regulation of components of the purinergic system in PBMCs during human sepsis.

How the COVID-19 pandemic affected the severity and clinical presentation of diverticulitis.

BACKGROUND/AIMS: Single-institution studies showed that patients presented with more severe diverticulitis and underwent more emergency operations during the coronavirus disease 2019 (COVID-19) pandemic. Therefore, we studied this trend using nationwide data from the American College of Surgeons National Surgical Quality Improvement Program database. METHODS: Patients (n = 23,383) who underwent a colectomy for diverticulitis in 2018 (control year) and 2020 (pandemic year) were selected. We compared these groups for differences in disease severity, comorbidities, perioperative factors, and complications. RESULTS: During the pandemic, colonic operations for diverticulitis decreased by 13.14%, but the rates of emergency operations (17.31% vs. 20.04%, P< 0.001) and cases with a known abscess/perforation (50.11% vs. 54.55%, P< 0.001) increased. Likewise, the prevalence of comorbidities, such as congestive heart failure, acute renal failure, systemic inflammatory response syndrome, and septic shock, were higher during the pandemic (P< 0.05). During this same period, significantly more patients were classified under American Society of Anesthesiologists classes 3, 4, and 5, suggesting their preoperative health states were more severe and life-threatening. Correspondingly, the average operation time was longer (P< 0.001) and complications, such as organ space surgical site infection, wound disruption, pneumonia, acute renal failure, septic shock, and myocardial infarction, increased (P< 0.05) during the pandemic. CONCLUSIONS: During the pandemic, surgical volume decreased, but the clinical presentation of diverticulitis became more severe. Due to resource reallocation and possibly patient fear of seeking medical attention, diverticulitis was likely underdiagnosed, and cases that would have been elective became emergent. This underscores the importance of monitoring patients at risk for diverticulitis and intervening when criteria for surgery are met.

Adenosine metabolized from extracellular ATP ameliorates organ injury by triggering A2BR signaling.

BACKGROUND: Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A2BR. The aim of this study was to evaluate the role of CD39 and CD73 delivering adenosine to A2BRs in regulating the host's response to T/HS. METHODS: T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A2BR) and conditional knockout (intestinal epithelial cell-specific deficient VillinCre-A2BRfl/fl) mice. At 3 three hours after resuscitation, blood and tissue samples were collected to analyze organ injury. RESULTS: T/HS upregulated the expression of CD39, CD73, and the A2BR in organs. ATP and adenosine levels increased after T/HS in bronchoalveolar lavage fluid. CD39, CD73, and A2BR mimics/agonists alleviated lung and liver injury. Antagonists or the CD39, CD73, and A2BR knockout (KO) exacerbated lung injury, inflammatory cytokines, and chemokines as well as macrophage and neutrophil infiltration and accumulation in the lung. Agonists reduced the levels of the liver enzymes aspartate transferase and alanine transaminase in the blood, whereas antagonist administration or CD39, CD73, and A2BR KO enhanced enzyme levels. In addition, intestinal epithelial cell-specific deficient VillinCre-A2BRfl/fl mice showed increased intestinal injury compared to their wild-type VillinCre controls. CONCLUSION: In conclusion, the CD39-CD73-A2BR axis protects against T/HS-induced multiple organ failure.

Pharmacological modulation of P2X4 in inflammatory bowel diseases: the way towards novel therapeutics?

Inflammatory bowel diseases (IBDs) are a group of idiopathic, chronic, relapsing, inflammatory conditions, which include ulcerative colitis (UC) and Crohn's disease (CD). These disorders are characterised by intestinal symptoms associated with chronic inflammation of the intestinal mucosa, such as gut dysmotility and visceral pain. Currently, the pharmacological management of IBD patients is far from satisfactory in terms of efficacy and safety, thus spurring the interest of the scientific community to identify novel molecular targets for the management of these disorders. According to recent research, it appears that P2 purinergic receptors, which can regulate the host's response to inflammation, have been identified as potential targets for the treatment of IBDs. In particular, among P2 receptors, the P2X4 receptor subtype has recently captured the attention of the research community owing to its role in shaping immune/inflammatory responses. Based on this evidence, the present review has been conceived to provide a critical appraisal of the available knowledge about the role of P2X4R subtype in the pathophysiological mechanisms underlying IBDs, pointing out its potential as therapeutic target to develop innovative therapeutic strategies aimed at counteracting the inflammatory process, gut dysmotility and visceral hypersensitivity associated with these disorders.

Assessment of Risk Factors for Iatrogenic Genitourinary Injuries During a Proctectomy.

BACKGROUND: It is critical to avoid iatrogenic injuries affecting genitourinary organs in order to prevent postoperative urinary or sexual dysfunction, which lead to lengthier recovery and possibly reoperation. METHODS: Using the 2016-2019 American College of Surgeons National Quality Improvement Program (ACS NSQIP) Targeted Proctectomy Database, we collated 2577 patients with non-metastatic rectal cancer who underwent a laparoscopic or open proctectomy. Univariate analysis was used to identify differences in perioperative factors and genitourinary injuries (GUIs) between operative approaches, and multivariate logistic regression was used to identify independent risk factors for sustaining an intraoperative GUI. RESULTS: The rates of preoperative comorbidities were significantly higher among patients who received an open operation. The proportion of GUIs was also significantly higher in this patient population. Multivariate logistic regression demonstrated that patients who underwent a laparoscopic proctectomy were associated with a 51.4% lower risk of sustaining a GUI. Furthermore, >10% body weight loss in the past 6 months and ASA class 3 status were independently associated with a higher risk of GUI regardless of operation type. CONCLUSION: Patients who undergo a laparoscopic proctectomy are associated with a lower risk of GUI. On the other hand, patients with >10% body weight loss and ASA class 3: Severe Systemic Disease were associated with a higher risk of GUI.

The Effects of the COVID-19 Pandemic on Mastectomy Outcomes for Breast Cancer.

BACKGROUND: Single center studies have shown that during the Coronavirus Disease 2019 (COVID-19) pandemic, many patients had surgical procedures postponed or modified. We studied how the pandemic affected the clinical outcomes of breast cancer patients who underwent mastectomies in 2020. METHODS: Using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database, we compared clinical variables of 31,123 and 28,680 breast cancer patients who underwent a mastectomy in 2019 and 2020, respectively. Data from 2019 served as the control, and data from 2020 represented the COVID-19 cohort. RESULTS: Fewer surgeries of all kinds were performed in the COVID-19 year than in the control (902,968 vs. 1,076,411). The proportion of mastectomies performed in the COVID-19 cohort was greater than in the control year (3.18% vs. 2.89%, <0.001). More patients presented with ASA level 3 in the COVID-19 year vs. the control (P < .002). Additionally, the proportion of patients with disseminated cancer was lower during the COVID-19 year (P < .001). Average hospital length of stay (P < .001) and time from operation to discharge were shorter in the COVID vs. control cohort (P < .001). Fewer unplanned readmissions were seen in the COVID year (P < .004). CONCLUSION: The ongoing surgical services and mastectomies for breast cancer during the pandemic produced similar clinical outcomes to those seen in 2019. Prioritization of resources for sicker patients and the use of alternative interventions produced similar results for breast cancer patients who underwent a mastectomy in 2020.

Comparing carotid endarterectomies with or without shunting in symptomatic and asymptomatic patients.

BACKGROUND: Recent research shows that placement of an intraluminal shunt during a carotid endarterectomy (CEA) can be associated with postoperative complications. Therefore, we compared CEA operations with or without shunting to further analyze their clinical outcomes. METHODS: From the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database, 13,736 cases between 2016 and 2019 were analyzed to compare adult symptomatic and asymptomatic carotid stenosis patients who underwent a CEA operation, with or without shunt placement. RESULTS: Rates of stroke with a neurological deficit (p = 0.012), myocardial infarction (p = 0.021), and urinary tract infection (p = 0.030) were higher among symptomatic patients with shunting. Multivariate logistic regression revealed that risk of CNI was higher among both symptomatic (93.63%, p < 0.001) and asymptomatic (69.58%, p = 0.001) patients with shunting, irrespective of confounding variables. CONCLUSION: Shunting was found to be associated with higher rates of postoperative complications in both symptomatic and asymptomatic patient populations.

A Single-Institution Comparison of Robot-Assisted and Conventional Laparoscopic Colorectal Surgeries.

There has been ongoing discussion regarding the superiority of robotic laparoscopic surgery (RLS) over conventional laparoscopic surgery (CLS) in many surgical subspecialties. We therefore sought to elucidate if RLS is associated with more favorable clinical outcomes than CLS among patients who underwent colorectal surgery. Using data from a high-volume single institution in New Jersey, we identified 145 patients who underwent an elective RLS or CLS sigmoid resection for colon cancer or diverticulitis in 2019 and 2020. We analyzed operation time, hospitalization cost, complications, readmissions, reoperations, and lymph node retrieval. Operation time and operation to discharge time were not significantly different among patients undergoing surgery for colon cancer (P > .05), but operation time was found to be longer in diverticulitis patients (P = .03). Additionally, RLS was significantly more costly ($86,003 ± $3520 vs. $68,277 ±$1,168, P < .001) for patients with diverticulitis. Our data demonstrate that the benefit of RLS over CLS in colon resections for diverticulitis and colon cancer is not evident due to the increased costs associated with RLS procedures.

The impact of gender on clinical outcomes after sustaining a pelvic fracture.

INTRODUCTION: In trauma care, pelvic fractures contribute to morbidity and mortality. Since men and women have different pelvic structures and hormonal milieu, we studied if these gender differences affect clinical outcomes after pelvic fractures. METHODS: Using the 2016 American College of Surgeons Trauma Quality Improvement Program (ACS TQIP) database, we stratified 24,425 patients with pelvic fractures by gender. Male and female patients were analyzed for differences in comorbidities,  mechanism of injury, complications, and other clinical parameters. RESULTS: Female patients were older (p < 0.001) and had more comorbidities (p < 0.001), such as bleeding disorder, congestive heart failure, chronic obstructive pulmonary disorder, dementia, chronic renal failure, diabetes mellitus, and hypertension. Although female patients were sicker before sustaining pelvic fractures, male patients had higher rates of post-trauma complications (p < 0.001), such as acute kidney injury, deep vein thrombosis, unplanned admission to the intensive care unit (ICU), and unplanned return to the operating room (OR). Multivariate logistic regression further supports this as male gender was independently associated with a 26.1% higher risk of developing at least one complication (p < 0.001), despite having a higher average Injury Severity Score (ISS) (21.91 ± 0.09 versus 20.71 ± 0.11, p < 0.001). Interestingly, male patients also had a longer hospital length of stay than female patients (13.36 ± 0.12 days versus 11.8 2± 0.14 days, p < 0.001). CONCLUSION: Even though female patients were older and had more pre-existing comorbidities, male patients developed more complications and had longer hospital stays. Trial registration number Not a clinical trial.

Comparison of Robotic and Laparoscopic Colectomies Using the 2019 ACS NSQIP Database.

OBJECTIVES: Robot-assisted laparoscopic surgeries (RLSs) have become increasingly common in the past decade alongside conventional laparoscopic surgeries (CLSs). In general, RLSs have been reported to be superior to CLSs; therefore, we compared both methods among patients undergoing an elective colectomy for differences in perioperative factors and postoperative complications. METHODS: A retrospective analysis was conducted using the 2019 American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. We stratified 5879 patients into two cohorts according to their preoperative diagnosis of either colon cancer or chronic diverticulitis. Patients within each group were further stratified by operative approach. RESULTS: Of the 5879 patients, 3210 colon cancer and 2669 chronic diverticulitis patients underwent an elective colectomy. There were no differences in length of stay and time from operation to discharge between RLSs and CLSs. RLSs, however, had significantly longer operation times (minutes; colon cancer: RLS 242.9 ± 91.0 vs CLS 177.4 ± 78.2, P < 0.001; chronic diverticulitis: RLS 226.2 ± 87.4 vs CLS 181.7 ± 74.4, P < 0.001). Among all of the colon cancer patients, RLS had higher rates of unplanned return to the operating room (P = 0.028) and organ space surgical site infection (P = 0.035). Among chronic diverticulitis patients, RLS was associated with higher rates of postoperative sepsis, anastomotic leak, organ space surgical site infection, and unplanned readmission (all P < 0.05). CONCLUSIONS: CLS may be the more efficient operative technique because it was associated with a shorter average operation time and fewer postoperative complications. This paradigm, however, may change as the robotic technology develops and surgeons become more experienced with RLS.

A 2A ADENOSINE RECEPTORS REGULATE MULTIPLE ORGAN FAILURE AFTER HEMORRHAGIC SHOCK IN MICE.

ABSTRACT: Trauma hemorrhagic shock (T/HS) is a clinical condition that causes multiple organ failure that needs rapid intervention. Restricted oxygen at the cellular level causes inflammation and subsequent cell death. Adenosine triphosphate is the universal intracellular energy currency and an important extracellular inflammatory signaling molecule. Adenosine, an endogenous nucleotide formed as a result of the breakdown of adenosine triphosphate, is also released during T/HS. Adenosine binds to four G protein-coupled receptors (A 1R , A 2a , A 2b , A 3R ) called adenosine receptors or P1 receptors. In the present study, we evaluated the effect of activation, inactivation, and genetic absence of A2aR (A2aR -/- mice) on T/HS-induced multiple organ failure. Wild-type mice were pretreated (30 min before shock induction) with an agonist or antagonist and then subjected to T/HS by withdrawing arterial blood and maintaining the blood pressure between 28 and 32 mm Hg. A2aR -/- mice were subjected to T/HS in the absence of pharmacologic treatment. Neutrophil sequestration was assessed by detecting myeloperoxidase, and Evans blue dye (EBD) method was used to analyze lung permeability. Blood and lung inflammatory cytokine levels were determined by sandwich enzyme-linked immunosorbent assay. The liver enzymes aspartate aminotransferase and alanine aminotransferase were determined spectrophotometrically from plasma. Activation of the apoptotic cascade was evaluated using a mouse apoptosis array. Our results demonstrate that the selective A2aR agonist CGS21680 decreases lung neutrophil sequestration, lung proinflammatory cytokines IL-6 and TNF-α, and bronchoalveolar lavage EBD. Pretreatment with the selective antagonist ZM241385 and genetic blockade in A2aR -/- mice increased neutrophil sequestration, proinflammatory cytokine levels, and bronchoalveolar lavage fluid EBD. The myeloperoxidase level in the lung was also increased in A2aR -/- mice. We observed that antiapoptotic markers decreased significantly with the absence of A2aR in the lung and spleen after T/HS. In conclusion, our data demonstrate that activation of A2aR regulates organ injury and apoptosis in the setting of T/HS.

A2A adenosine receptor activation prevents neutrophil aging and promotes polarization from N1 towards N2 phenotype.

Extracellular adenosine is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsis. Extracellular adenosine has potent immunosuppressive effects by binding to and activating G protein-coupled A2A adenosine receptors (A2AARs) on the surface of neutrophils. A2AAR signaling reproduces many of the phenotypic changes in neutrophils that are characteristic of sepsis, including decreased degranulation, impaired chemotaxis, and diminished ability to ingest and kill bacteria. We hypothesized that A2AARs also suppress neutrophil aging, which precedes cell death, and N1 to N2 polarization. Using human neutrophils isolated from healthy subjects, we demonstrate that A2AAR stimulation slows neutrophil aging, suppresses cell death, and promotes the polarization of neutrophils from an N1 to N2 phenotype. Using genetic knockout and pharmacological blockade, we confirmed that A2AARs decrease neutrophil aging in murine sepsis induced by cecal ligation and puncture. A2AARs expression is increased in neutrophils from septic patients compared to healthy subject but A2AAR expression fails to correlate with aging or N1/N2 polarization. Our data reveals that A2AARs regulate neutrophil aging in healthy but not septic neutrophils.

Vessel Sealant Devices in Thyroidectomies: An ACS-NSQIP Study.

OBJECTIVES: Thyroidectomies involve meticulous dissection of a highly vascularized organ and complications may develop, such as hematoma, hypocalcemia, and even hypoparathyroidism. Because some of these complications may be fatal, we sought to identify the differences in postthyroidectomy outcomes when the use of a vessel sealant device (VSD) such, as LigaSure or Harmonic scalpel, is compared with more traditional techniques, such as ligatures and clips. METHODS: Using the 2016 American College of Surgeons National Surgical Quality Improvement Program Targeted Thyroidectomy database, we compared patients who underwent a thyroidectomy using a VSD with patients without a VSD for differences in postoperative complications. RESULTS: A total of 5146 cases were identified and 3452 of those cases used a VSD, whose use was associated with significantly lower rates of hematoma, deep vein thrombosis, and hypocalcemia before discharge, as well as a shorter length of stay and longer operation time. Multivariate logistic regression showed that VSD was associated with 32.27% and 39.15% lower odds of hypocalcemia and hematoma, respectively. VSDs also were used more frequently in cases that had multinodular, severe, or substernal goiter or Graves disease as the primary indication for surgery and in patients with a higher body mass index. There was no significant difference in the incidence of recurrent laryngeal nerve injury between the two groups. CONCLUSIONS: Analysis of the American College of Surgeons National Surgical Quality Improvement Program data indicates that VSDs are associated with a lower risk of complications, such as hypocalcemia, hematoma, and deep vein thrombosis, suggesting that VSDs may be a more effective method of hemostasis than traditional techniques.

Cathepsin D interacts with adenosine A2A receptors in mouse macrophages to modulate cell surface localization and inflammatory signaling.

Adenosine A2A receptor (A2AR)-dependent signaling in macrophages plays a key role in the regulation of inflammation. However, the processes regulating A2AR targeting to the cell surface and degradation in macrophages are incompletely understood. For example, the C-terminal domain of the A2AR and proteins interacting with it are known to regulate receptor recycling, although it is unclear what role potential A2AR-interacting partners have in macrophages. Here, we aimed to identify A2AR-interacting partners in macrophages that may effect receptor trafficking and activity. To this end, we performed a yeast two-hybrid screen using the C-terminal tail of A2AR as the "bait" and a macrophage expression library as the "prey." We found that the lysosomal protease cathepsin D (CtsD) was a robust hit. The A2AR-CtsD interaction was validated in vitro and in cellular models, including RAW 264.7 and mouse peritoneal macrophage (IPMΦ) cells. We also demonstrated that the A2AR is a substrate of CtsD and that the blockade of CtsD activity increases the density and cell surface targeting of A2AR in macrophages. Conversely, we demonstrate that A2AR activation prompts the maturation and enzymatic activity of CtsD in macrophages. In summary, we conclude that CtsD is a novel A2AR-interacting partner and thus describe molecular and functional interplay that may be crucial for adenosine-mediated macrophage regulation in inflammatory processes.

Anti-inflammatory Effects of Novel P2X4 Receptor Antagonists, NC-2600 and NP-1815-PX, in a Murine Model of Colitis.

The pharmacological blockade of P2X4 receptors has shown potential benefits in the management of several immune/inflammatory diseases. However, data regarding the involvement of P2X4 receptors in the pathophysiological mechanisms of action in intestinal inflammation are not well defined. We aimed to evaluate the anti-inflammatory effects of two novel and selective P2X4 receptor antagonists, NC-2600 and NP-1815-PX, and characterize the molecular mechanisms of their action in a murine model of 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis. These two drugs and dexamethasone (DEX) were administered orally for 6 days, immediately after the manifestation of DNBS. The body weight decrease, resulting from colitis, was attenuated by NC-2600 and NP-1815-PX, but not DEX. However, all three drugs attenuated the increase in spleen weight and ameliorated macroscopic and microscopic colonic tissue damage. Furthermore, all three compounds decreased tissue IL-1ß levels and caspase-1 expression and activity. Colonic tissue increase of tumor necrosis factor was downregulated by DEX, while both NC-2600 and NP-1815-PX were ineffective. The reduction of occludin associated with colitis was ameliorated by NC-2600 and NP-1815-PX, but not DEX. In THP-1 cells, lipopolysaccharide and ATP upregulated IL-1ß release and NLRP3, caspase-1, caspase-5, and caspase-8 activity, but not of caspase-4. These changes were prevented by NC-2600 and NP-1815-PX treatment. For the first time, the above findings show that the selective inhibition of P2X4 receptors represents a viable approach to manage bowel inflammation via the inhibition of NLRP3 inflammasome signaling pathways.