Instillation Of Acid Research Articles

Coriolus Versicolor Downregulates TLR4/NF-κB Signaling Cascade in Dinitrobenzenesulfonic Acid-Treated Mice: A Possible Mechanism for the Anti-Colitis Effect.

Inflammatory bowel diseases (IBDs) are disorders characterized by chronic inflammation of the intestinal tract. The focus of the present study was to examine the effect of the fungus Coriolus versicolor (CV), underlining its correlation with Toll-like receptors 4 (TLR4) and nuclear factor erythroid 2-related factor 2 (Nrf2); we aim to evaluate its anti-inflammatory and antioxidant effect in mice exposed to experimental colitis. The model was induced in mice by colon instillation of dinitrobenzenesulfonic acid (DNBS), CV was administered orally (200 mg per kg) daily for 4 days. On day 4, the animals were killed, and the tissues collected for histological, biochemical, and molecular analyses. Four days after DNBS administration, CC motif chemokine ligand 2 (CCL2), prostaglandin E2 (PGE2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) production increased in association with damage to the colon. Neutrophil infiltration, as assessed by myeloperoxidase (MPO) activity, in the mucosa was associated with overexpression of P-selectin and intercellular adhesion molecule 1 (ICAM1). Immunohistochemistry for nitrotyrosine and poly-(ADP-Ribose)-polymerase (PARP) showed evident stain in the inflamed colon. Treatment with CV significantly reduced the appearance of colon changes and weight loss. These effects were associated with a remarkable ability of CV to reduce the expression of TLR4 and modulate the pathway of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). This improved the colon architecture, reduced MPO activity, the release of proinflammatory cytokines, the presence of nitrotyrosine, and the hyperactivation of PARP, as well as the up-regulation of P-selectin and ICAM1. Furthermore, we studied the action of CV on the Nrf2/HO-1 pathway, which is important for maintaining redox balance, demonstrating that CV by significantly increasing both enzymes is able to counteract the oxidative stress induced by DNBS. Taken together, our results clearly show that this natural compound can be considered as a possible dietary supplement against colitis.

Acute Toxicity in the Rat Lung Induced by Intratracheal Instillation of Glycolic Acid.

Inhalation toxicity tests of glycolic acid, which is used in many household products, have been reported, but the pulmonary toxicity of glycolic-acid has not been confirmed. Here, the lung damage caused by glycolic acid was investigated in rats. An intratracheal instillation test was performed with glycolic acid in male rats. Bronchoalveolar lavage fluid (BALF) and histopathological analysis were conducted to identify the pulmonary toxicities. Intratracheal instillation of glycolic acid caused weight loss in animals and increased the content of lactate dehydrogenase, total protein, polymorphonuclear neutrophils, and inflammatory cytokines in BALF. In addition, pulmonary edema, alveolar/interstitial inflammation, and necrosis and desquamation of bronchial/bronchiolar epithelia were confirmed via histopathological examination. Exposure to glycolic acid can be harmful and toxic to the lungs.

Ulcer-Healing Effect of Hydroalcoholic Extract and Essential Oil of Achillea millefolium L. on Murine Model of Colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease that can be treated with many medications but they have various side effects and low cure rate. So, the need for finding novel drugs with better healing characters and less toxicity would be mandatory. Achillea millefolium (A. millefolium, Yarrow) has been traditionally used to treat bleeding, ulcers, wounds, liver, and bile disorders, and recently it has been shown to have anti-ulcer, analgesic, anti-inflammatory, antioxidant, and appetizing effects that make it as a good candidate for UC. UC was induced with intra-rectal instillation of acetic acid. A. millefolium hydroalcoholic extract (AMHE, 200, 400, and 600 mg/kg/day) and essential oil (AMEO, 62.5, 125, and 250 μl/kg/day) were given to six groups of male Wistar rats for 5 days. Dexamethasone (1 mg/kg/day, intra-peritoneal) and mesalazine (100 mg/kg/day, orally) were used as reference drugs. Colon tissue specimens were separated for assessing macroscopic, pathologic, and biochemical markers. For AMHE, 77.2 mg/g equivalent to gallic acid was obtained for total phenols. Main assessed markers, including ulcer index, total colitis index, colon weight/length ratio, rats' weight gain, and malondialdehyde levels were significantly improved in AMHE (400 and 600 mg/kg/day) and AMEO (125 and 250 μl/kg/day) groups compared to controls. Myeloperoxidase activity was only attenuated in AMHE groups significantly. Both AMHE and AMEO were effective in healing experimental colitis. It seems antioxidant, anti-inflammatory, and anti-ulcer activities of Yarrow are responsible for these beneficial effects. Further studies are warranted to elucidate the exact mechanisms involved.

Changes in visual quality with soft contact lenses after the instillation of hyaluronic acid eye drops

PurposeTo evaluate the changes in visual function and anterior surface aberrations during soft contact lens (SCL) wear after the instillation of hyaluronic acid (HA) eye drops with different viscosity. MethodsA prospective, randomized, and participant-masked study was performed. Twenty healthy participants (25.4 ± 2.6 years) were evaluated. Hydrogel (Ocufilcon D) and silicone-hydrogel (Somofilcon A) SCL were randomly assigned to both eyes of the same participant. Visual function in terms of high- and low-contrast corrected distance visual acuity (CDVA) and anterior contact lens surface aberrations (RMS HOA) were measured before and after the instillation, at different times, of different eye drops: saline (control) and 0.1%, 0.2%, and 0.3% HA. ResultsCompared with the saline solution, during hydrogel SCL wear, there was an improvement (P < 0.05) in high-contrast CDVA after 3 and 10 min with 0.1% HA, and after 5 and 20 min with 0.2% HA. During silicone-hydrogel SCL wear, there was a deterioration (P < 0.05) in high-contrast CDVA after 1 and 30 min with 0.3% HA. Additionally, during silicone-hydrogel SCL wear, there was also a deterioration (P < 0.05) in low-contrast CDVA after 5 and 20 min with 0.3% HA. In terms of RMS HOA, there were no clinically relevant changes with both SCL. ConclusionsThe instillation of HA eye drops could have a different effect on visual quality depending on their concentration of HA, the contact lens material, its surface ionicity, or other physicochemical properties that should be studied in future studies.

Factors associated with treatment outcomes after intravesical hyaluronic acid therapy in women with refractory interstitial cystitis: A prospective, multicenter study.

Bladder instillation of hyaluronic acid (HA) is an acceptable treatment for bladder pain syndrome/interstitial cystitis (BPS/IC). The treatment is limited by a high proportion of non-responders (~30%-40%). Here, we aimed to evaluate predisposing factors associated with treatment outcomes. This is a prospective multicenter study. We enrolled a total of 137 (out of 140) women with refractory IC. They all underwent a standard protocol of 6-month intravesical HA therapy (initial 4 weeks, once weekly, followed by once monthly). To assess the outcomes, we used the pain Visual Analog Scale (Pain-VAS), Interstitial Cystitis Symptom and Problem Index (ICSI & ICPI), and a scaled Global Response Assessment (GRA). The age of patients was 47.6 ± 27.5 (range 24-77) years. We found statistically significant improvement (p < 0.001) in the Pain-VAS and the ICSI & ICPI scores both after the initial 4-weekly instillations and at the end of 6-month treatment. Those who reported moderate/marked improvement on GRA at the 2 follow-up visits were considered responders: 39.4% (n = 54) at the first follow-up, and 59.9% (n = 82) at the second follow-up. No remarkable side effect was noted. After statistical analyses, treatment outcomes on GRA were positively associated with baseline functional bladder capacity and with Pain-VAS scores. The initial treatment responses optimally (p < 0.001) predicted final treatment outcomes (McNemar). Intravesical HA therapy is safe and effective for most (~60%) of our patients with refractory IC. Functional bladder capacity and Pain-VAS scores before treatment, and the early treatment responses are helpful predictors of treatment outcomes.

Protective effects of curcumin against rat intestinal inflammation‑related motility disorders.

Intestinal inflammation frequently occurs alongside dysmotility, which is characterized by altered myosin light chain phosphorylation levels. Curcumin, an active component from the ginger family, is reported to confer anti-inflammatory effects. However, the effects of curcumin on both diarrhea and constipation associated inflammation remains to be elucidated. The present study was designed to investigate the effects of curcumin on diarrhea and constipation and to determine the related mechanisms. Sprague-Dawley rats were used to establish diarrhea and constipation models via intracolonic acetic acid (4%) instillation or cold water gavage for 2 weeks, respectively. Blood samples were collected to measure the serum levels of the cytokines TNF-α and IL-1β using ELISA kits. Western blotting was performed to measure NF-κB, RhoA, Rho-related kinase 2, phosphorylated MLC20, phosphorylated myosin phosphorylated target subunit 1, 130k Da-MLC kinase (MLCK), c-kit tyrosine kinase protein expression, and reverse transcription-quantitative PCR was conducted to measure MLCK expression levels. The results indicated that curcumin reversed the elevations in the pro-inflammatory cytokines IL-1β and TNF-α by inhibiting the NF-κB pathway in rats with diarrhea and constipation. The results also indicated that myosin light chain (MLC) phosphorylation in intestinal smooth muscle was positively and negatively associated with the motility of inflammation-related diarrhea and constipation in rats, respectively. Curcumin significantly reversed the increased MLC phosphorylation in the jejunum of the rats with diarrhea, significantly enhanced the reductions in inflammatory mediators, including TNF-α and IL-1β, of rats with constipation and significantly ameliorated the related hyper-motility and hypo-motility in rats with both diarrhea and constipation. In conclusion, the potential roles of the MLC kinase, c-kit tyrosine and Rho A/Rho-associated kinase 2 pathways, which are involved in curcumin-induced amelioration of inflammation-related diarrhea and constipation, were explored in the present study. Results from the present study suggested that curcumin has potential therapeutic value for treating intestinal inflammation and inflammation-related motility disorders.

Continuous saline bladder irrigation after blue light transurethral resection of bladder tumor increases recurrence-free survival in low- to intermediate-risk non-muscle invasive bladder cancer

To evaluate the efficacy of Continuous Saline Bladder Irrigation (CSBI) after blue light transurethral resection of bladder tumor (TURBT) to prevent recurrence of low- to intermediate-risk Non-Muscle Invasive Bladder Cancer (NMIBC). We conducted a retrospective study including patients with low- to intermediate-risk NMIBC who underwent TURBT in two urological centers between January 2017 and December 2018. Each TURBT was performed using blue light after intravesical instillation of hexaminolaevulinic acid. The experimental group included patients who received CSBI while the control group included patients without CSBI. When practice, CSBI was started immediately after the surgery and was interrupted 24 hours thereafter. Low-risk NMIBC had a surveillance while intermediate NMIBC had 8 adjuvant endovesical instillations of Mitomycin. The primary endpoint was bladder tumor recurrence free-survival which was defined as the time between the initial TURBT and the date of TURBT for bladder recurrence. A total of 167 patients (median age: 71 years) were included: 20% female, 15% low-risk, 85% intermediate-risk NMIBC. CSBI was performed in 95 cases (57%). No complication related to irrigation was reported. Bladder recurrence was observed in 55 cases (32.9%): 22 (23.1%) in the CSBI group vs. 33 (45.8%) in the control group (P=0.002). Multivariate stepwise logistic regression analysis with backward selection revealed that CSBI (HR 0.47 [0.27-0.81]; P=0.006) and MMC (HR 0.55 [0.31-0.95]; P=0.034) were significantly associated with reduced risk of bladder recurrence. Continuous saline bladder irrigation reduced the risk of bladder recurrence after blue light TURBT in patients with low- to intermediate-risk NMIBC while being safe. Prospective randomized study is needed to confirm these results. 3.

Evaluation of the therapeutic effects of mycophenolate mofetil targeting Nrf-2 and NLRP3 inflammasome in acetic acid induced ulcerative colitis in rats

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that increases the risk of colorectal cancer. UC is highly associated with the disturbance of the immune system leading to oxidative stress and chronic inflammation of intestine. Therefore, the current study was conducted to investigate the potential anti-oxidant and anti-inflammatory effects of MMF against acetic acid-induced UC that might be associated with the regulation of Nrf-2 and NLRP3 inflammasome signaling. UC was induced in Sprague-Dawley rats by intracolonic instillation of acetic acid. Forty-eight hours post UC induction, MMF (50 mg/kg/day, orally) was given for 8 consecutive days. Then, colon tissues and blood samples were collected. Results showed that MMF significantly attenuated the acetic acid-induced functional, biochemical, and inflammatory injuries in colon. MMF significantly decreased oxidative stress as indicated by the decreased malondialdehyde concentration and the increased total antioxidant capacity, glutathione, catalase, and superoxide dismutase concentrations in colon tissues. MMF also significantly increased Nrf-2 and decreased NLRP3 inflammasome expressions. Moreover, MMF decreased expression of interferon-gamma and increased expression of interferon-alpha. MMF also significantly decreased expression of pro-inflammatory cytokines, interleukin (IL)-1β and IL-18. These results suggest that MMF has antioxidant and anti-inflammatory effects against acetic acid-induced UC through the upregulation of Nrf-2, and INF-α expression in addition to the suppression of NLRP3 inflammasome and subsequent release of IL1β, IL-18 and INF-γ.

Repeated 5-aminolevulinic Acid Instillations During Follow-up in Non-muscle-invasive Bladder Cancer: A Randomized Study.

Non-muscle invasive bladder carcinoma (NMIBC) is highly recurrent. We studied if 5-aminolevulinic acid (5-ALA) instillations before transurethral resection of bladder tumours (TURBT) and cystoscopy extend the time to recurrence during follow-up with NMIBC patients. A prospective multicenter study enrolled 328 NMIBC patients. All TURBTs and control cystoscopies during the one-year study period were done with or without 5-ALA instillations. The primary endpoint was time to recurrence. The secondary endpoints were time to recurrence after 7.5, 10.5, and 13.5 months and the number of patients with progressive disease. The overall median follow-up time was 80.4 and 87.0 months for the control and study groups, respectively. There was no statistical difference in time to first recurrence between the two groups. We could not obtain significant differences between the control and 5-ALA groups in tumour recurrence among patients with NMIBC.

QUANTIFICATION OF CONJUNCTIVAL HYPEREMIA IN RABBITS USING ANALYSIS SOFTWARE

In a method evaluating conjunctival hyperemia using rabbits, it is common to visually grade the degree of vasodilation. However, this method is limited in evaluating consecutive value and in reproducibility. We quantified the degree of conjunctival hyperemia in rabbits as the area ratio of blood vessels by image analysis, and compared the vascular area percentage calculated by image analysis with the hyperemia score. The conjunctiva was photographed before and after the instillation of 0.1% arachidonic acid using a digital medical scope VersaCam® (Nidek Co., Ltd.). Next, the area of the conjunctival blood vessels occupying the area of interest was calculated using hyperemia analysis software. The hyperemia score was visually graded for the degree of conjunctiva vasodilation. Furthermore, the hyperemia score and the vascular area ratio were compared. Fifteen minutes after the instillation of arachidonic acid, the area ratio of the blood vessels in the conjunctiva increased significantly and gradually decreased over time. This trend correlated with the hyperemia score. We found that the degree of conjunctival hyperemia in rabbits can be evaluated numerically and quantitatively. This method is considered to be useful for evaluating conjunctival hyperemia in allergic conjunctival diseases.

Comparison of acute inhalation toxicity of sulfuric acid by the inhalation and intratracheal instillation methods.

Recently, intratracheal instillation has been focused on as a simple, low-cost alternative to the inhalation method. In this study, intratracheal instillation of sulfuric acid, a typical acidic compound, was performed to compare the acute toxicity of acidic compounds that could cause damage to the respiratory system between intratracheal instillation and inhalation. Sulfuric acid was administered to male rats at doses of 0.7, 2, 7, 20, and 60 mg/kg by dividing the total dose into four doses. General condition and body weight were examined up to 14 days after administration, and macropathological and histopathological examinations were performed. The half-lethal dose was then estimated. All animals administered 20 and 60 mg/kg sulfuric acid and one animal administered 2 mg/kg sulfuric acid died within 4 h after administration. No abnormalities were observed in other animals. At 20 and 60 mg/kg, multiple red foci or diffuse red areas were macroscopically observed in the lungs. In these lesions, histopathologically, clefts between the mucosal epithelium and basement membrane and necrosis of the alveolar epithelium were observed. Deaths in these groups may have resulted from lung injury. No notable changes were observed in other animals. Therefore, the half-lethal dose of sulfuric acid by intratracheal instillation was estimated as 7–20 mg/kg. The acute toxicity by intratracheal instillation was evaluated with two-fold sensitivity since the exposure at the half-lethal sulfuric acid concentration in inhalation studies was calculated as 43.2 mg/kg.

Identification of N-acyl-N-indanyl-α-phenylglycinamides as selective TRPM8 antagonists designed to mitigate the risk of adverse effects

Transient receptor potential melastatin 8 (TRPM8), a temperature-sensitive ion channel responsible for detecting cold, is an attractive molecular target for the treatment of pain and other disorders. We have previously discovered a selective TRPM8 antagonist, KPR-2579, which inhibited bladder afferent hyperactivity induced by acetic acid instillation into the bladder. However, additional studies have revealed potential adverse effects with KPR-2579, such as the formation of a reactive metabolite, CYP3A4 induction, and convulsions. In this report, we describe the optimization of α-phenylglycinamide derivatives to mitigate the risk of these adverse effects. The optimal compound 13x exhibited potent inhibition against icilin-induced wet-dog shakes and cold-induced frequent voiding in rats, with a wide safety margin against the potential side effects.

Comparison of intravesical instillation of hyaluronic acid with intradetrusor botulinum toxin A injection or cystoscopic hydrodistention for ketamine-associated cystitis.

ObjectiveThis study aimed to compare the therapeutic effect of intravesical instillation hyaluronic acid with intradetrusor botulinum toxin A (BTX-A) injection or cystoscopic hydrodistention for ketamine-associated cystitis.MethodsThirty-six patients were evenly randomly divided into the BTX-A group or the hydrodistention group. Patients received 200 U BTX-A detrusor injections in the BTX-A group and cystoscopic hydrodistention in the hydrodistention group. Intravesical instillation of hyaluronic acid was administrated in both groups for eight times. Patients with involuntary detrusor contraction were divided into the persistent involuntary detrusor contraction group and resolved involuntary detrusor contraction group after treatment in 6 months. The predictors of persistent involuntary detrusor contraction were analyzed.ResultsTwelve months after treatment, the daytime frequency, Interstitial Cystitis Symptom Index, maximal capacity, and maximal cystometric capacity in the BTX-A group were significantly better than those in the hydrodistention group. Patients with resolution of involuntary detrusor contraction had a significantly shorter duration of ketamine, lower amount of fibrosis in pathology, and higher maximal capacity than those with persistent involuntary detrusor contraction 6 months after therapy.ConclusionIntravesical instillation of hyaluronic acid with intradetrusor BTX-A injection appears to be a preferable option for long-term effectiveness compared with cystoscopic hydrodistention.

Halogenated Agent Delivery in Porcine Model of Acute Respiratory Distress Syndrome via an Intensive Care Unit Type Device.

Acute respiratory distress syndrome (ARDS) is a common cause of hypoxemic respiratory failure and death in critically ill patients, and there is an urgent need to find effective therapies. Preclinical studies have shown that inhaled halogenated agents may have beneficial effects in animal models of ARDS. The development of new devices to administer halogenated agents using modern intensive care unit (ICU) ventilators has significantly simplified the dispensing of halogenated agents to ICU patients. Because previous experimental and clinical research suggested potential benefits of halogenated volatiles, such as sevoflurane or isoflurane, for lung alveolar epithelial injury and inflammation, two pathophysiologic landmarks of diffuse alveolar damage during ARDS, we designed an animal model to understand the mechanisms of the effects of halogenated agents on lung injury and repair. After general anesthesia, tracheal intubation, and the initiation of mechanical ventilation, ARDS was induced in piglets via the intratracheal instillation of hydrochloric acid. Then, the piglets were sedated with inhaled sevoflurane or isoflurane using an ICU-type device, and the animals were ventilated with lung-protective mechanical ventilation during a 4 h period. During the study period, blood and alveolar samples were collected to evaluate arterial oxygenation, the permeability of the alveolar-capillary membrane, alveolar fluid clearance, and lung inflammation. Mechanical ventilation parameters were also collected throughout the experiment. Although this model induced a marked decrease in arterial oxygenation with altered alveolar-capillary permeability, it is reproducible and is characterized by a rapid onset, good stability over time, and no fatal complications. We have developed a piglet model of acid aspiration that reproduces most of the physiological, biological, and pathological features of clinical ARDS, and it will be helpful to further our understanding of the potential lung-protective effects of halogenated agents delivered through devices used for inhaled ICU sedation.

Chronic suppurative otomastoiditis due to nontuberculous mycobacteria: A case series

IntroductionEight new cases of chronic otomastoiditis due to nontuberculous mycobacteria were reported at Center Hospitalier Universitaire Sainte-Justine (CHUSJ) between 2008 and 2018. In the literature, only 89 cases have been described since 1972. This case series aims to define the clinical presentation, infectious pathogens, as well as diagnostic and therapeutic means employed in cases of nontuberculous mycobacteria otitis media encountered in our tertiary pediatric reference center. MethodsAll cases of otitis media caused by nontuberculous mycobacteria diagnosed at Sainte-Justine between 2008 and 2018 were reviewed. Species identification was retrieved from the Laboratoire de Santé Publique du Québec, Quebec's provincial public health and reference laboratory. ResultsAll 8 cases occurred in immunocompetent children. Clinical features on presentation were chronic tympanostomy tube otorrhea with abundant granulation tissue in 7 cases. CT scan demonstrated coalescent mastoiditis in 3 cases. The median delay between initial presentation and identification of nontuberculous mycobacteria was 81 days. Seven patients had a Mycobacterium (M.) abscessus complex infection. Treatment consisted of weekly microscopic granulation debridement, a combined systemic antibiotic therapy for an average duration of 21 weeks, as well as instillation of boric acid into the middle ear. While 3 cases required at least one mastoidectomy, 2 cases were treated only medically. ConclusionNontuberculous mycobacteria otitis media is a rare clinical entity, for which high clinical suspicion and specific microbiological analyses could minimize diagnostic delay. The use of boric acid as a desiccating agent may allow for a better local control.

Pulmonary pyruvate metabolism as an index of inflammation and injury in a rat model of acute respiratory distress syndrome.

Increased pulmonary lactate production is correlated with severity of lung injury and outcome in acute respiratory distress syndrome (ARDS) patients. This study was conducted to investigate the relative contributions of inflammation and hypoxia to the lung's metabolic shift to glycolysis in an experimental animal model of ARDS using hyperpolarized (HP) 13 C MRI. Fifty-three intubated and mechanically ventilated male rats were imaged using HP 13 C MRI before, and 1, 2.5 and 4 hours after saline (sham) or hydrochloric acid (HCl; 0.5 ml/kg) instillation in the trachea, followed by protective and nonprotective mechanical ventilation (HCl-PEEP and HCl-ZEEP) or the start of moderate or severe hypoxia (Hyp90 and Hyp75 groups). Pulmonary and cardiac HP lactate-to-pyruvate ratios were compared among groups for different time points. Postmortem histology and immunofluorescence were used to assess lung injury severity and quantify the expression of innate inflammatory markers and local tissue hypoxia. HP pulmonary lactate-to-pyruvate ratio progressively increased in rats with lung injury and moderate hypoxia (HCl-ZEEP), with no significant change in pulmonary lactate-to-pyruvate ratio in noninjured but moderately hypoxic rats (Hyp90). Pulmonary lactate-to-pyruvate ratio was elevated in otherwise healthy lung tissue only in severe systemic hypoxia (Hyp75 group). ex vivo histological and immunopathological assessment further confirmed the link between elevated glycolysis and the recruitment into and presence of activated neutrophils in injured lungs. HP lactate-to-pyruvate ratio is elevated in injured lungs predominantly as a result of increased glycolysis in activated inflammatory cells, but can also increase due to severe inflammation-induced hypoxia.

Chromium (D-Phenylalanine)3 supplementation attenuates acetic acid induced ulcerative colitis in rats: In silico docking and dynamic studies using NF-kB

Chromium-D-phenylalanine [Cr(D-phe)] is known to be anti-diabetic, anti-inflammatory and antioxidant complex. Our preliminary work reveals the beneficial effect of Cr(D-phe) in indomethacin-induced enterocolitis. The present work was intended to explore the effect of Cr(D-phe) in acetic acid-induced ulcerative colitis in rats. Further, molecular docking simulation experiments were performed. Colitis was induced through intra-rectal instillation of acetic acid (3% v/v) and the effectiveness of Cr(D-phe)(30, 60 and 90 μg/kg) and sulphasalazine was measured using clinical, macroscopic, biochemical, contractility and histopathological studies. In addition, drug likeliness, molecular docking and dynamic studies of Cr(D-phe) and sulphasalazine with NF-kappa B (1NFK) were carried out. Pretreatment of different doses of Cr(D-phe)showed significant reduction (P&amp;#60;0.01; P&amp;#60;0.001) in clinical, macroscopic score, oxidative stress and elevated biochemical parameters. Protective nature of Cr(D-phe)was further confirmed by histopathological examination and colonic contractility studies. In silico studies reveals that Cr(D-phe)exhibited better docking score (-14.121) compared to sulphasalazine (-5.654). Dug likeliness studies showed that Cr(D-phe)passes lipinski’s rule and exhibited better bioavailability properties with negligible hepatotoxicity compared to standard. Molecular dynamic studies reveal that Cr(D-phe)showed better stability compared to standard compound, while interacting with 1NFK for 10 ns. The observed beneficial activity of Cr(D-phe)could be due to its anti-oxidative and anti-inflammation by preventing NF-kB activity.

Effect of positive end-expiratory pressure on functional residual capacity in two experimental models of acute respiratory distress syndrome.

ObjectiveMeasurement of positive end-expiratory pressure (PEEP)-induced recruitment lung volume using passive spirometry is based on the assumption that the functional residual capacity (FRC) is not modified by the PEEP changes. We aimed to investigate the influence of PEEP on FRC in different models of acute respiratory distress syndrome (ARDS).MethodsA randomized crossover study was performed in 12 pigs. Pulmonary (n = 6) and extra-pulmonary (n = 6) ARDS models were established using an alveolar instillation of hydrochloric acid and a right atrium injection of oleic acid, respectively. Low (5 cmH2O) and high (15 cmH2O) PEEP were randomly applied in each animal. FRC and recruitment volume were determined using the nitrogen wash-in/wash-out technique and release maneuver.ResultsFRC was not significantly different between the two PEEP levels in either pulmonary ARDS (299 ± 92 mL and 309 ± 130 mL at 5 and 15 cmH2O, respectively) or extra-pulmonary ARDS (305 ± 143 mL and 328 ± 197 mL at 5 and 15 cmH2O, respectively). The recruitment volume was not significantly different between the two models (pulmonary, 341 ± 100 mL; extra-pulmonary, 351 ± 170 mL).ConclusionsPEEP did not influence FRC in either the pulmonary or extra-pulmonary ARDS pig model.

Post-treatment with a heat shock protein 90 inhibitor prevents chronic lung injury and pulmonary fibrosis, following acute exposure of mice to HCl

Aim/Purpose: Exposure to high levels of hydrochloric acid (HCl) is associated with severe lung injury including both acute inflammation and chronic lung disease, which leads to the development of pulmonary fibrosis. Currently, there are no specific therapeutic agents for HCl-induced lung injury. Heat shock protein 90 (HSP90) has been implicated in the pathogenesis of pulmonary fibrosis. Thus, we have used a murine model of intra-tracheal acid instillation to investigate the antidotal effects of AUY-922, a small molecule HSP90 inhibitor, already in clinical trials for various types of cancer, against HCl-induced chronic lung injury and pulmonary fibrosis.Methods: HCl (0.1 N, 2 μl/g body weight) was instilled into male C57Bl/6J mice at day 0. After 24 h, mice began receiving 1 mg/kg AUY-922, 2x/week for 15 or 30 days.Results: AUY-922 suppressed the HCl-induced sustained inflammation, as reflected in the reduction of leukocyte and protein concentrations in bronchoalveolar lavage fluid, and inhibited the activation of pro-fibrotic biomarkers, ERK and HSP90. Furthermore, AUY-922 improved lung function, decreased the overexpression and accumulation of extracellular matrix proteins and dramatically reduced histologic evidence of fibrosis in the lungs of mice exposed to HCl.Conclusions: We conclude that AUY-922, and possibly other HSP90 inhibitors, successfully block the adverse effects associated with acute exposures to HCl and may represent an effective antidote against HCl-induced chronic lung injury and fibrosis.

Does acid reflux precipitate ischaemia in subjects with acute coronary syndrome?

It has been postulated that gastro-oesophageal reflux disease (GORD) may trigger coronary ischaemia through viscerocardiac reflex vasoconstriction in subjects with ischaemic heart disease (IHD). Our aim was to estimate the prevalence of GORD in subjects with IHD who present with acute coronary syndrome (ACS) and to determine whether GORD may serve as a trigger for ischaemic events. Twenty patients with isolated reflux oesophagitis and 39 with acute coronary syndrome (ACS with concomitant GORD) were studied. Twenty-two subjects comprising normal volunteers and those who were admitted for minor surgical trauma were used as normal controls. All subjects underwent oesophago-gastroduodenal endoscopy (EGD) and acid instillation with hydrochloric acid (0.1 M), as well as nuclear imaging (sestaMIBI) with technetium99. Ischaemia was detected by ST depression using ECG monitoring for one hour during and immediately after EGD. Of the 111 subjects with ACS, 39 (35.1%) had erosive GORD and comprised the study group. Subjects with ACS had more incidence of diabetes (p = 0.001), hypertension (p = 0.002), a history of smoking (p = 0.006) and elevated serum triglyceride levels (p = 0.008) compared to the GORD group. Risk-factor clustering in the form of the metabolic syndrome was more common in ACS subjects (44 vs 5%; p = 0.008). ST depression was documented in 8/39 (20.5%) patients in the ACS group and 5/20 (25%) in the GORD group (p = 0.958). Reversible perfusion defects on sestaMIBI scan were seen in 35.6% of the ACS subjects. Although GORD is common in subjects with ACS, we have not been able to show that GORD may serve as a trigger for ischaemia in these subjects.