Instillation Of Acid Research Articles

The short-term efficacy of intravesical instillation of hyaluronic acid treatment for bladder pain syndrome/interstitial cystitis.

The aim of the study was to evaluate the short term efficacy of intravesical instillation of hyaluronic acid in patients with Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC). The study included 54 women with BPS/IC who received intravesical instillation of hyaluronic acid treatment (120 mg/50 mL) for 6 weeks. Visual Analogue Scale (VAS), The O'Leary Sant Questionnaire (ICSI/ICPI) forms of the patients were filled by the clinician and the health technician separately before and 3 months after the treatment. Demographic characteristics of the patients were recorded, and effectiveness of the treatment was investigated according to these data. Decrease in mean VAS and mean total scores of ICSI and ICPI was observed after three months of intravesical instillation of hyaluronic acid treatment (55%, p<0.05 and 48.5%, p<0.05 and 45.5%, p<0.05, respectively). In most of the patients, all scores of VAS, ICSI and ICPI improved (minimum: 75.9%, maximum: 94.4%). Mostly the symptoms of nocturia and pollakiuria were seen, and treated after the instillation treatment. It has been observed that in the short-term follow-up of intravesical instillation of hyaluronic acid treatment, the symptoms have highly improved. Also, Turkish versions of ICSI and ICPI forms were reliable and comprehensible.

Effect of Ethanolic Extract of Seeds of Solanum torvum in Acetic Acid induced Ulcerative Colitis in Male Wistar Rats

Objective: To elucidate the protective effect of ethanolic extract of dried seeds of Solanum torvum (S. torvum) in acetic acid-induced ulcerative colitis in male Wistar rats. Methods: The animals were divided into various treatment groups (n=5). Rats were administered with 2ml of acetic acid (4%) via intrarectal route. Prednisolone was used as a standard drug and S. torvum was administered at a dose of 100 and 300mg/kg, p.o. Macroscopic score, colon weight to length ratio, colonic superoxide dismutase (SOD), reduced glutathione (GSH), myeloperoxidase (MPO), catalase (CAT), and lipid peroxidation (TBARS) levels and histopathological changes were recorded after the treatment regimen of 11 days.Results: Intrarectal instillation of acetic acid caused significant (P

Thymol has beneficial effects on the experimental model of ulcerative colitis.

Objective:Thymol, a natural aromatic monoterpene phenol derived from thymus, possesses anti-inflammatory benefits. Here, we evaluated the potential of thymol therapy in improving an animal model of ulcerative colitis. Materials and Methods:Luminal instillation of acetic acid was used to induce colitis in male Wistar rats. Treatment groups daily received prednisolone (2 mg/kg, orally) or thymol (100 mg/kg, orally) for 10 consecutive days. Then, the rats were euthanized and tissue specimens were collected for evaluation of cyclooxygenase-2 (COX-2) expression by immunohistochemistry. Furthermore, the levels of total protein, nitric oxide, myeloperoxidase, malondialdehyde, IL-1, IL-6, and TNF-α were monitored in colonic homogenates. Eventually, the relative mRNA expression of IκBα and NF-κBp65 was investigated using reverse-transcriptase PCR (RT-PCR) in colonic homogenates. Results:Both medications could reduce the mortality rate and the clinical scores of ulcerative colitis. The COX-2 expression was significantly reduced in the colons of thymol-treated animals compared to the prednisolone group. Also, the myeloperoxidase activity, nitric oxide level and malondialdehyde intensity were decreased in the colons of thymol-treated animals to a greater extent compared to the prednisolone group. Moreover, the total protein content of guts showed significant increases in the guts of thymol-treated animals in comparison to the prednisolone group. Nonetheless, thymol significantly reduced the levels of IL-6, and IL-1 compared to prednisolone. Both medications caused a significant decrease in the mRNA level of NF-κBp65, though the mRNA level of IκBα did not show significant changes between the groups.Conclusion:Thymol may be a promising agent to ameliorate ulcerative colitis.

Enhanced endoscopic imaging for urothelial cancer

The precise identification and detection of bladder tumours is a prerequisite for complete transurethral resection and, thus, the reduction of recurrence. White-light cystoscopy remains the gold standard and has been further improved by the introduction of digital HD techniques. New digital techniques such as narrow-band imaging (NBI) or the IMAGE 1 S-System have been introduced to better visualise suspicious areas. They are particularly valuable in the outpatient setting. However, fluorescence or photodynamic diagnostics (PDD) after instillation of hexaminolevulinic acid into the bladder is the only approach supported by good evidence. It is recommended by most guidelines in high-grade tumours or carcinoma in situ, while the value of NBI and the Image 1 S-System is under evaluation. Newer approaches include microscopic techniques such as optical coherence tomography, confocal laser endomicroscopy or molecular imaging. The combination of these methods with macroscopic imaging could be very promising.

The POTENTIAL OF CAESALPINIA CRISTA LEAVES IN THE TREATMENT OF ULCERATIVE COLITIS IN LABORATORY ANIMALS

The aim of present investigation was to study the Ulcerative colitis effect of extracts of Caesalpinia crista in acetic acid induced experimental colitis in Sprague Dawley rats. Sprague Dawley rats were divided into nine groups (n=6). The rats were received 7 days pretreatment with chloroform, ethyl acetate, ethanolic extracts of C. crista 200 mg/kg and 400 mg/kg. Ulcerative colitis was induced by intrarectal administration of 1ml of 4% acetic acid solution on 8th day. Prednisolone (2 mg/kg) was used as standard drug administered orally for 3 days. After 48 hrs of colitis induction animals were sacrificed by cervical dislocation to remove colon and distal 5 cm of the colon was dissected. Macroscopical study, Ulcer index of the colon, colonic myeloperoxidase (MPO) and malondialdehyde (MDA) level in colon tissue and blood were studied. Intrarectal instillation of acetic acid caused enhanced ulcer index, myeloperoxidase and malondialdehyde. Ethanol extract of C.crista showed significant effect in lowering ulcer index as well as neutrophil infiltration at a dose of 400 mg/kg in acetic acid induced colitis. The present investigation demonstrates that the ethanol extract of C.crista is of potent therapeutic value in the amelioration of experimental colitis in rat by inhibiting the inflammatory mediator.

Protective effect of Mumiju against acetic acid-induced ulcerative colitis in rats.

In this study, we elucidated the ameliorative effect of aqueous extract of leaves of Mumiju against acetic acid-induced experimental colitis in male rats. The animals were randomly divided into four groups (n=7) including I: control group, II: vehicle group (injected with 2 ml acetic acid (4%) intra rectally), III and IV: treatment groups which received Mumiju (250 mg/kg) orally or intraperitoneally for 4 consecutive days after ulcer induction. Ulcer index, severity of inflammation, colonic levels of superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA), and histological changes were recorded after the treatment regimen of 4 days. The ulcer index, severity of inflammation and colonic MDA levels were increased following intrarectal instillation of acetic acid. Also, acetic acid significantly decreased the SOD and GSH levels. Treatment with Mumiju for 4 days exhibited significantly lowered oxidative stress, while elevated of SOD and GSH levels. Regenerative-healing patterns also was seen by histopathological findings after treatment with Mumiju. The present investigation demonstrates that Mumiju could be regarded as a herb with potent therapeutic value in the amelioration of experimental colitis in laboratory animals by modulation of oxidant- antioxidant system.

Distinctive Roles and Mechanisms of Human Neutrophil Peptides in Experimental Sepsis and Acute Respiratory Distress Syndrome.

To examine the effects and mechanisms of human neutrophil peptides in systemic infection and noninfectious inflammatory lung injury. Prospective experimental study. University hospital-based research laboratory. In vitro human cells and in vivo mouse models. Wild-type (Friend virus B-type) and conditional leukocyte human neutrophil peptides transgenic mice were subjected to either sepsis induced by cecal ligation and puncture or acute lung injury by intratracheal instillation of hydrochloric acid followed by mechanical ventilation. Using human neutrophil peptides as bait, the basal cell adhesion molecule (CD239) and the purinergic P2Y purinoceptor 6 receptor were identified as the putative human neutrophil peptides receptor complex in human lung epithelial cells. In the cecal ligation and puncture sepsis model, Friend virus B-type mice exhibited higher systemic bacterial load, cytokine production, and lung injury than human neutrophil peptides transgenic mice. Conversely, an increased lung cytokine production was seen in Friend virus B-type mice, which was further enhanced in human neutrophil peptides transgenic mice in response to two-hit lung injury induced by hydrochloric acid and mechanical ventilation. The human neutrophil peptides-mediated inflammatory response was mediated through the basal cell adhesion molecule-P2Y purinoceptor 6 receptor signal pathway in human lung epithelial cells. Human neutrophil peptides are critical in host defense against infectious sepsis by their cationic antimicrobial properties but may exacerbate tissue injury when neutrophil-mediated inflammatory responses are excessive in noninfectious lung injury. Targeting the basal cell adhesion molecule/P2Y purinoceptor 6 signaling pathway may serve as a novel approach to attenuate the neutrophil-mediated inflammatory responses and injury while maintaining the antimicrobial function of human neutrophil peptides in critical illness.

Potential of Mimosa pudica leaf in the treatment of ulcerative colitis in rat

&lt;p class="Abstract"&gt;The aim of present investigation was to validate its folk use in the treatment of ulcerative colitis in the rat model. Sprague Dawley rats were divided into nine groups with six animals in each group. The rats received seven days of pretreatment with chloroform, ethyl acetate or ethanolic extract of &lt;em&gt;Mimosa pudica&lt;/em&gt;. For induction of ulcerative colitis, rats were administered with 2 mL of 4% acetic acid solution intrarectally. Ulcer index, macroscopical study of the colon, myeloperoxidase and malondialdehyde levels in colon tissue and blood, and histopathology of the colon tissue were studied. Intrarectal instillation of acetic acid caused increased ulcer index, colonic myeloperoxidase and malondialdehyde. Pretreatment with &lt;em&gt;M. pudica&lt;/em&gt; ethanolic extract (400 mg/kg) significantly lowered the ulcer index, colonic myeloperoxidase and malondialdehyde as compared with the standard drug prednisolone. The present investigation demonstrates that the ethanol extract of &lt;em&gt;M. pudica&lt;/em&gt; leaf is effective in the treatment of ulcerative colitis.&lt;/p&gt;&lt;p class="Abstract"&gt;&lt;strong&gt;Video Clip of Methodology:&lt;/strong&gt;&lt;/p&gt;&lt;p class="Abstract"&gt;Embedding or block making: 24 sec &lt;a href="https://www.youtube.com/v/Y1I4tKYMLsE"&gt;Full Screen&lt;/a&gt; &lt;a href="https://www.youtube.com/watch?v=Y1I4tKYMLsE"&gt;Alternate&lt;/a&gt;&lt;/p&gt;&lt;p class="Abstract"&gt;Tissue processing: 19 sec &lt;a href="https://www.youtube.com/v/7nYpxL2qPhg"&gt;Full Screen&lt;/a&gt; &lt;a href="https://www.youtube.com/watch?v=7nYpxL2qPhg"&gt;Alternate&lt;/a&gt;&lt;/p&gt;&lt;p class="Abstract"&gt;Section cutting: 33 sec &lt;a href="https://www.youtube.com/v/_amFL9kNLBw"&gt;Full Screen&lt;/a&gt; &lt;a href="https://www.youtube.com/watch?v=_amFL9kNLBw"&gt;Alternate&lt;/a&gt;&lt;/p&gt;

Complete reversal of the clinical symptoms and image morphology of ketamine cystitis after intravesical hyaluronic acid instillation

Rationale:Ketamine abuse is an emerging issue in many countries, and ketamine cystitis (KC) is a growing disease which more and more urologists may encounter with. There was no gold standard diagnostic criteria of ketamine cystits established yet, but well-accepted with the positive substance abuse history and clinical symptoms. The clinical presentation of ketamine cystitis varies and may mimic those presented in interstitial cystitis (IC), such as voiding frequency, urgency with urge incontinence, dysuria, nocturia, burning sensation during urination, post urination pain, painful hematuria, and small bladder capacity, but there are still differences that KC presented with more urgency, hematuria, pyuria and upper urinary tract involvement such as ureteral stenosis, vesico-ureteric reflux, hydronephrosis and renal function impairment.Patient concerns:We presented an interesting case with a 36-year-old man who's symptoms mimic acute prostatitis but there was no positive pathogen been cultured. The computed tomography (CT) findings revealed asymmetrical bladder wall thickening, which misleading us to the impression of bladder cancer. After the cystoscopy with bladder biopsy, the pathology revealed severe inflammation without malignancy. After that, we prescribed anticholinergic agent, beta-3 agonist and nonsteroidal anti-inflammatory drug (NSAID) for him, but in vain.Diagnoses:Erosive cystitis with prominent infiltration by eosinophils, lymphocytes, neutrophils and plasma cells.Interventions:Then we introduced hyaluronic acid (HA) instillation, once a week for total 10 times.Outcomes:After the treatment, his urgency, frequency, nocturia improved and his bladder capacity increased from less than 100ml to 350mL per urination. The following magnetic resonance imaging (MRI) and bladder biopsy result revealed complete reversal.Lessons:To our literature review, this is the first case of ketamine cystitis presented with asymmetrical bladder wall thickening, which may be considered as an irreversible change, but turns out complete reversal of the clinical symptoms and image morphology after merely intravesical hyaluronic acid instillation

Promising therapeutic effect of gold nanoparticles against dinitrobenzene sulfonic acid-induced colitis in rats.

Aim: The aim of this study is to evaluate the therapeutic effect of two different doses of naked gold nanoparticles (AuNPs) in the experimental colitis in rats. Materials & methods: Colitis was induced in rats by single intracolonic instillation of dinitro-benzene sulfonic acid (250μl DNBS-25mg/rat). 4 days later the rats were intravenously injected with a single dose of AuNPs 40 and 400μg/kg of size 16-25nm. Results: In comparison with dinitro-benzene sulfonic acid-colitis group, the exposure to AuNPs for 72 h ameliorated the liver and kidney functions, increased the regenerative capacity of damaged colon tissues, suppressed the inflammatory cytokine response and diminished the colonic malondialdehyde and myeloperoxidase activities. In addition, there was a remarkable improvement in the antioxidant defense system. Conclusion: Our study suggested a new therapy for experimental colitis without noticeable drawbacks.

Therapeutic potential of dinitrobenzene sulfonic acid (DNBS)-induced colitis in mice by targeting IL-1β and IL-18

Interleukin (IL)-1 and IL-18 belong to the IL-1 family of ligands, and their receptors are members of the IL-1 receptor family. Both cytokines drive an extensive range of pro-inflammatory networks in many cell types using common signal transduction cascades. Anyway, differences in signaling pathways exist. With this aim in mind, we investigated by using transgenic mice the mechanisms through the simultaneous deficiency of both IL-1β and IL-18 could be more protective compared to blocking the single cytokine IL-1β or IL-18 during colitis.Colitis was provoked in mice by instillation of dinitrobenzene sulfonic acid (DNBS) in the colon. The results indicated that single knockout (KO) mice of IL-1β or IL-18, and double KO mice of both IL-1β and IL-18 were hyporesponsive to DNBS-induced colitis compared to wild type (WT) mice, in which double KO were less sensitive than single KO mice. Moreover, treatment with Anakinra (IL-1R antagonist) also ameliorated colitis, in views of macroscopic and histological alteration, infiltration of neutrophils or Th1 cells, oxidative and nitrosative stress. Anakinra more significantly reduced cyclooxygenase (COX-2) and nuclear factor (NF-κB) levels as well as IKB-α degradation compared to blocking IL-18. On the contrary, the absence of IL-18 reduced p-ERK and p-p38 mitogen-activated protein kinase (MAPKs) in a more significant way compared to blocking IL-1β. Thus, the double KO increased the protective effects against colon inflammation maybe because different converging inflammatory pathways are being inhibited.In conclusion, the blocking of both IL-1β and IL-18 function may be advantageous in the treatment of IBD or inflammatory diseases.

Characterization of the seven-day course of pulmonary response following unilateral lung acid injury in rats.

BackgroundAspiration of gastric acid is an important cause of acute lung injury. The time course of the pulmonary response to such an insult beyond the initial 48 hours is incompletely characterized. The purpose of this study was to comprehensively describe the pulmonary effects of focal lung acid injury over a seven day period in both directly injured and not directly injured lung tissue.MethodsMale Wistar rats underwent left-endobronchial instillation with hydrochloric acid and were sacrificed at 4, 24, 48, 96 or 168 h after the insult. Healthy non-injured animals served as controls. We assessed inflammatory cell counts and cytokine levels in right and left lung lavage fluid and blood, arterial oxygen tension, alterations in lung histology, lung wet-to-dry weight ratio and differential lung perfusion.ResultsLung acid instillation induced an early strong inflammatory response in the directly affected lung, peaking at 4–24 hours, with only partial resolution after 7 days. A less severe response with complete resolution after 4 days was seen in the opposite lung. Alveolar cytokine levels, with exception of IL-6, only partially reflected the localization of lung injury and the time course of the functional and histologic alterations. Alveolar leucocyte subpopulations exhibited different time courses in the acid injured lung with persistent elevation of alveolar lymphocytes and macrophages. After acid instillation there was an early transient decrease in arterial oxygen tension and lung perfusion was preferentially distributed to the non-injured lung.ConclusionThese findings provide a basis for further research in the field of lung acid injury and for studies exploring effects of mechanical ventilation on injured lungs. Incomplete recovery in the directly injured lung 7 days after acid instillation suggests that increased vulnerability and susceptibility to further noxious stimuli are still present at that time.

Systematic review and practice policy statements on urinary tract infection prevention in adults with spina bifida.

Urinary tract infection (UTI) is a source of morbidity and healthcare costs in adults with spina bifida (ASB). UTI prevention strategies are often recommended, but the evidence of various approaches remains unclear. We performed a systematic review to inform a best practice policy statement for UTI prevention in ASB. On behalf of the Neurogenic Bladder Research Group (NBRG.org), we developed an a priori protocol and searched the published English literature for 30 outcomes questions addressing UTI prevention in ASB. The questions spanned the categories of antibiotics, oral supplements, bladder management factors and social support. Where there was little literature in ASB, we included literature from similar populations with neurogenic bladder (NB). Data was abstracted and then reviewed with recommendations made by consensus of all authors. Level of Evidence (LoE) and Grade of Recommendation (GoR) were according to the Oxford grading system. Of 6,433 articles identified by our search, we included 99 publications. There was sufficient evidence to support use of the following: saline bladder irrigation (LoE 1, GoR B), gentamicin bladder instillation (LoE 3, GoR C), single-use intermittent catheterization (IC) (LoE 2, GoR B), hydrophilic catheters for IC (LoE 2, GoR C), intradetrusor onabotulinumtoxinA injection (LoE 3, GoR C), hyaluronic acid (HA) instillation (LoE 1, GoR B), and care coordination (LoE 3, GoR C). There was sufficient evidence to recommend against use of the following: sterile IC (LoE 1, GoR B), oral antibiotic prophylaxis (LoE 2, GoR B), treatment of asymptomatic bacteriuria (LoE 2, GoR B), cranberry (LoE 2, GoR B), methenamine salts (LoE 1, GoR B), and ascorbic acid (LoE1, GoR B). There was insufficient evidence to make a recommendation for other outcomes. Overall, there are few studies in UTI prevention in the specific population of ASB. Research in populations similar to ASB helps to guide recommendations for UTI prevention in the challenging patient group of ASB. Future studies in UTI prevention specific to ASB are needed and should focus on areas shown to be of benefit in similar populations.

The efficacy of intravesical hyaluronic acid instillation in resistant bladder pain syndrome

Purpose: In this study the authors aimed to assess the efficacy of intravesical hyaluronic acid (HA) instillation in patients with resistant painful bladder syndrome (PBS). Materials and Methods: A series of 32 women with PBS received intravescical instillation of HA once-a-week for eight weeks and then once monthly for four months for a total of 12 doses. The authors considered scale (VAS) pain scores ≥ 4 and total scores (symptom and bother scores) ≥ 13 on the pelvic pain and urgency/frequency (PUF) questionnaire. An efficacy of the HA instillation was evaluated by comparing the mean changes in the scores of the VAS and questionnaires from baseline to eight weeks of treatment. Improvement was defined as a ≥ 2 decrease in the VAS. Results: The authors compared the responses at baseline and after treatment: there were 22 patients (63.0%) with positive response rate at week 8, which was maintained until 12 months. Specifically, both VAS and PUF score decreased significantly after treatment. Conclusion: The present results showed that intravesical HA therapy is an effective treatment for patients with PBS who had inadequate response to conservative treatment.

PD19-11 ISOLATED TRIGONE ONABOTULINUMTOXINA INJECTION DOES NOT ADVERSELY CHANGE AMBULATORY VOIDING FUNCTION IN A RAT MODEL OF OVERACTIVE BLADDER

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology I1 Apr 2018PD19-11 ISOLATED TRIGONE ONABOTULINUMTOXINA INJECTION DOES NOT ADVERSELY CHANGE AMBULATORY VOIDING FUNCTION IN A RAT MODEL OF OVERACTIVE BLADDER Amy D. Dobberfuhl, Xiaoyuan Han, Edward C. Diaz, Bertha Chen, and Craig V. Comiter Amy D. DobberfuhlAmy D. Dobberfuhl More articles by this author , Xiaoyuan HanXiaoyuan Han More articles by this author , Edward C. DiazEdward C. Diaz More articles by this author , Bertha ChenBertha Chen More articles by this author , and Craig V. ComiterCraig V. Comiter More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1001AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES OnabotulinumtoxinA (BTX) chemodenervation is an established third-line therapy for overactive bladder. The aim of our study was to further characterize the physiologic effect of various BTX injection distributions on ambulatory and cystometric voiding function in conscious awake rats. METHODS Adult female rats (n=36) were divided into six groups. Treatment animals received injection of 7.5 units BTX (in 25-125 µL saline; 25 µL/aliquot): intact control, saline vehicle control, unilateral BTX, trigone BTX, posterior-lateral BTX, whole bladder BTX. Micturition frequency and volume were assessed using metabolic cages at baseline (day 0, 7) and following injection (day 14, 21, 28). Bladder function was then assessed using anesthetized acetic acid cystometry. RESULTS There was no overall correlation between rat weight and mean voided volume (r = -0.02, p = 0.81). Small volume voids were significantly associated with increased food intake (r = -0.21, p = 0.006) and greater stool output (r = -0.23, p = 0.003). Mean nocturnal voided volume was similar in control, vehicle, trigone and posterior-lateral groups. The ability to void small volumes was preserved in both the control and treatment groups with the exception of unilateral and whole bladder injection which demonstrated increased minimum voided volumes. On cystometry, mean voided volume was the greatest in the control and trigone groups prior to acetic acid. Increased threshold pressure was noted in both unilateral and whole bladder injection groups. Post void residual was decreased in all groups after acetic acid. The lowest number of voids and longest interval between voids was noted after unilateral and whole bladder BTX injection. Cystometric intercontractile interval correlated with increased nocturnal mean voided volume before (r = 0.33, p = 0.05) and after (r = 0.24, p = 0.17) acetic acid. Cystometric mean voided volume correlated with ambulatory nocturnal voided volume, however was almost 10-fold lower after saline instillation (r = 0.18, p = 0.30), and more closely approximated ambulatory voiding after acetic acid instillation (r = 0.30, p = 0.08). CONCLUSIONS Unilateral and whole bladder BTX injection resulted in elevated ambulatory nocturnal mean voided volumes, with higher pressure and smaller volume voids noted on cystometry. Trigone and posterior-lateral BTX injection patterns appear to preserve contractility, with threshold and peak contraction pressures similar to control animals. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e400 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Amy D. Dobberfuhl More articles by this author Xiaoyuan Han More articles by this author Edward C. Diaz More articles by this author Bertha Chen More articles by this author Craig V. Comiter More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Capturing the multifactorial nature of ARDS - "Two-hit" approach to model murine acute lung injury.

Severe acute respiratory distress syndrome (ARDS) presents typically with an initializing event, followed by the need for mechanical ventilation. Most animal models of ALI are limited by the fact that they focus on a singular cause of acute lung injury (ALI) and therefore fail to mimic the complex, multifactorial pathobiology of ARDS. To better capture this scenario, we provide a comprehensive characterization of models of ALI combining two injuries: intra tracheal (i.t.) instillation of LPS or hypochloric acid (HCl) followed by ventilator‐induced lung injury (VILI). We hypothesized, that mice pretreated with LPS or HCl prior to VILI and thus receiving a (“two‐hit injury”) will sustain a superadditive lung injury when compared to VILI. Mice were allocated to following treatment groups: control with i.t. NaCl, ventilation with low peak inspiratory pressure (PIP), i.t. HCl, i.t. LPS, VILI (high PIP), HCl i.t. followed by VILI and LPS i.t. followed by VILI. Severity of injury was determined by protein content and MPO activity in bronchoalveolar lavage (BAL), the expression of inflammatory cytokines and histopathology. Mice subjected to VILI after HCl or LPS instillation displayed augmented lung injury, compared to singular lung injury. However, mice that received i.t. LPS prior to VILI showed significantly increased inflammatory lung injury compared to animals that underwent i.t. HCl followed by VILI. The two‐hit lung injury models described, resulting in additive but differential acute lung injury recaptures the clinical relevant multifactorial etiology of ALI and could be a valuable tool in translational research.

KPR-2579, a novel TRPM8 antagonist, inhibits acetic acid-induced bladder afferent hyperactivity in rats.

Transient receptor potential melastatin 8 (TRPM8) is proposed to be a promising therapeutic target for hypersensitive bladder disorders. We examined the effects of KPR-2579, a novel selective TRPM8 antagonist, on body temperature and on mechanosensitive bladder single-unit afferent activities (SAAs) provoked by intravesical acetic acid (AA) instillation in rats. Female Sprague-Dawley rats were used. Effects of cumulative intravenous (i.v.) administrations of KPR-2579 (0.03-1 mg/kg) on deep body temperature were investigated (N = 18). In separate animals, effects of bolus administration of KPR-2579 (0.03 or 0.3 mg/kg, i.v.) on bladder hyperactivity induced by intravesical instillation of 0.1% AA were investigated using cystometry (N = 57) in a conscious free-moving condition or urethane-anesthetized condition, and SAA measurements (N = 41) were performed in a urethane-anesthetized condition. KPR-2579 at any doses tested did not affect body temperature. In cystometry measurements, a high dose (0.3 mg/kg) of KPR-2579 counteracted the shortened intercontraction interval provoked by AA instillation. In SAA measurements, 48 single afferent fibers (n = 24 in each fiber) were isolated. AA instillations significantly increased the SAAs of C fibers, but not of Aδ fibers, in the presence of KPR-2579's vehicle and a low dose (0.03 mg/kg) of KPR-2579. Pretreatment with a high dose (0.3 mg/kg) of KPR-2579 significantly inhibited the AA-induced activation of C-fiber SAAs. The present results suggest that TRPM8 channels play a role in the AA-induced pathological activation of mechanosensitive bladder C fibers in rats. KRP-2579 may be a promising drug for hypersensitive bladder disorders.

Instillation of hyaluronan reverses acid instillation injury to the mammalian blood gas barrier.

Acid (HCl) aspiration during anesthesia may lead to acute lung injury. There is no effective therapy. We hypothesized that HCl instilled intratracheally in C57BL/6 mice results in the formation of low-molecular weight hyaluronan (L-HA), which activates RhoA and Rho kinase (ROCK), causing airway hyperresponsiveness (AHR) and increased permeability. Furthermore, instillation of high-molecular weight hyaluronan (H-HA; Yabro) will reverse lung injury. We instilled HCl in C57BL/6 wild-type (WT), myeloperoxidase gene-deficient (MPO-/-) mice, and CD44 gene-deficient (CD44-/-) mice. WT mice were also instilled intranasally with H-HA (Yabro) at 1 and 23 h post-HCl. All measurements were performed at 1, 5, or 24 h post-HCl. Instillation of HCl in WT but not in CD44-/- resulted in increased inflammation, AHR, lung injury, and L-HA in the bronchoalveolar lavage fluid (BALF) 24 h post-HCl; L-HA levels and lung injury were significantly lower in HCl-instilled MPO-/- mice. Isolated perfused lungs of HCl instilled WT but not of CD44-/- mice had elevated values of the filtration coefficient ( Kf). Addition of L-HA on the apical surface of human primary bronchial epithelial cell monolayer decreased barrier resistance ( RT). H-HA significantly mitigated inflammation, AHR, and pulmonary vascular leakage at 24 h after HCl instillation and mitigated the increase of Kf and RT, as well as ROCK2 phosphorylation. Increased H- and L-HA levels were found in the BALF of mechanically ventilated patients but not in healthy volunteers. HCl instillation-induced lung injury is mediated by the L-HA-CD44-RhoA-ROCK2 signaling pathway, and H-HA is a potential novel therapeutic agent for acid aspiration-induced lung injury.

The Beneficial Effects of Hypiran in Ameliorating Rat Model of Ulcerative Colitis

Background: Different studies have been done on Hypericum anti-depressant effects, but only a few ones have documented in vivo anti-inflammatory properties of Hypericum following systemic administration. Objectives: This survey was designed to evaluate the potential effects of Hypiran, a hydro-alcoholic extract of St. John’s Wort, for the treatment and controlling inflammation in animal models of ulcerative colitis. Methods: In this experimental study, ulcerative colitis was induced in the male Wistar rats by luminal instillation of acetic acid. Animals in the treatment groups received Hypiran (150 mg/kg PO) or Prednisolone (4 mg/kg PO) daily for 10 consecutive days. At the end, the rats were sacrificed and the disease activity index, the levels of malondialdehyde, myeloperoxidase, nitric oxide, total protein and the concentration of TNF-α, IL-1β and IL-6 were assessed in the colonic homogenized tissue specimens. Results: The results showed that both therapies with Hypiran and Prednisolone could regress the clinical scores and the mortality rate of ulcerative colitis in a comparable manner. The levels of TNF-α, IL-1β and myeloperoxidase activity were down-regulated in the guts of Prednisolone treated rats more than Hypiran groups. Nevertheless, Hypiran decreased the levels of IL-6, nitric oxide and malondialdehyde more significantly than Prednisolone. Conclusions: Collectively, these data suggest that the Hypiran may be used as a natural source to alleviate the signs of rat model of ulcerative colitis.

Inhibition of the Receptor for Advanced Glycation End-Products in Acute Respiratory Distress Syndrome: A Randomised Laboratory Trial in Piglets

Background: The receptor for advanced glycation end products (RAGE) modulates the pathogenesis of acute respiratory distress syndrome (ARDS). RAGE inhibition was recently associated with attenuated lung injury and restored alveolar fluid clearance (AFC) in a mouse model of ARDS. However, clinical translation will first require assessment of this strategy in larger animals. Methods: Forty-eight anaesthetised Landrace piglets were randomised into a control group and three treatment groups. Animals allocated to treatment groups underwent orotracheal instillation of hydrochloric acid i) alone; ii) in combination with intravenous administration of a RAGE antagonist peptide (RAP), a S100P-derived peptide that prevents activation of RAGE by its ligands, or iii) in combination with intravenous administration of recombinant soluble (s)RAGE that acted as a decoy receptor. The primary outcome measure was net AFC at 4 h. Arterial oxygenation was assessed hourly for 4 h and alveolar-capillary permeability, alveolar inflammation, lung histology and lung mRNA expression of the epithelial sodium channel (α1-ENaC), α1-Na,K-ATPase and aquaporin (AQP)-5 were assessed at 4 h. Findings: Treatment with either RAP or sRAGE improved net AFC rates (median [interquartile range], 21.2 [18.8-21.7] and 19.5 [17.1-21.5] %/h, respectively, versus 12.6 [3.2-18.8] %/h in injured, untreated controls), improved oxygenation and decreased alveolar inflammation and histological evidence of tissue injury after acid-induced ARDS. RAGE inhibition also restored lung mRNA expression of α1-Na, K-ATPase and AQP-5. Interpretation: RAGE inhibition restored AFC and attenuated lung injury in a piglet model of acid-induced ARDS. Funding: Auvergne Regional Council, Agence Nationale de la Recherche, Direction Generale de l'Offre de Soins. Declaration of Interest: No conflict of interest, other source of financial support, corporate involvement, patent holdings, etc. is to be declared for all authors. Ethical Approval: Animals were maintained and all procedures were performed with the approval of the ethics committee of the French Ministere de l’Education Nationale, de l’Enseignement Superieur et de la Recherche in the Centre International de Chirurgie Endoscopique, School of Medicine - University of Clermont-Ferrand (approval number 01505.03). All experiments were performed in accordance with the “Animal Research: Reporting In Vivo Experiments” (ARRIVE) guidelines.