Inflammation & Allergy-Drug Targets (v.12, #5)

Piceatannol Modulates Lung Epithelial Cellular Responses to Pseudomonas aeruginosa by Pouya Sadeghi Aval, Jeff Werner, Ashley Cerqueira, Jazmyn Balfour-Boehm, Marina Ulanova (297-307).
Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen, which is the major cause of severechronic lung infection in cystic fibrosis patients. It is also responsible for systemic infections in immunocompromisedindividuals and those presenting with significant pulmonary conditions in intensive care units. This microorganism has thecapacity to initiate severe inflammation in infected lungs resulting in detrimental tissue damage. We have hypothesizedthat Syk protein tyrosine kinase mediates lung epithelial cellular responses to P. aeruginosa infection, and that a naturallyoccurring non-toxic Syk inhibitor piceatannol can protect infected human cells against the deleterious effects associatedwith this infection. We infected Syk-positive H292 or Syk-negative A549 human lung epithelial cell lines with P.aeruginosa and assessed the resulting cellular responses, i.e. production of proinflammatory cytokines, adhesion moleculeexpression, generation of reactive oxygen species, and apoptosis of infected cells, utilizing a multiplex bead-basedimmunoassay and flow cytometry. We also studied the internalization of P. aeruginosa using the gentamicin exclusionassay. We found that the piceatannol treatment significantly suppressed inflammation, oxidative stress and apoptosis inH292, but not in A549 cells implicating Syk participation in the regulation of the pathological processes induced by P.aeruginosa infection. Intriguingly, piceatannol was able to down-regulate the internalization of P. aeruginosa by bothSyk-positive and Syk-negative cell lines, implying that the mechanisms of action of this compound extend beyond Sykinhibition. As piceatannol can interfere with several mechanisms of bacterial pathogenesis this natural compound deservesfurther study as a potential therapeutic option in P. aeruginosa infection.

Green Tea Catechins Quench the Fluorescence of Bacteria-Conjugated Alexa Fluor Dyes by Lin Zhao, Wei Li, Shu Zhu, Sheena Tsai, Jianhua Li, Kevin J. Tracey, Ping Wang, Saijun Fan, Andrew E. Sama, Haichao Wang (308-314).
Accumulating evidence suggests that Green tea polyphenolic catechins, especially the (-)-epigallocatechingallate (EGCG), can be cross-linked to many proteins, and confer a wide range of anti-bacterial activities possibly bydamaging microbial cytoplasmic lipids and proteins. At the doses that conferred protection against lethal polymicrobialinfection (induced by cecal ligation and puncture), EGCG significantly reduced bacterial loads particularly in the liver andlung. To elucidate its bactericidal mechanisms, we determined whether EGCG affected the fluorescence intensities ofbacteria-conjugated Alexa Fluor 488 or 594 dyes. When mixed with unconjugated Alexa Fluor 488 or 594 dyes, EGCG oranalogs did not affect the fluorescence intensity of these dyes. In a sharp contrast, EGCG and some analogs (e.g.,Catechin Gallate, CG), markedly reduced the fluorescence intensity of Gram-positive Staphylococcus aureus-conjugatedAlexa 594 and Gram-negative Escherichia coli-conjugated Alexa 488. Interestingly, co-treatment with ethanol impairedthe EGCG-mediated fluorescence quenching of the G+ S. aureus, but not of the G- E. coli-conjugated Alexa Flour dyes. Inlight of the notion that Alexa Fluor dyes can be quenched by aromatic amino acids, it is plausible that EGCG exerts antimicrobialactivities possibly by altering microbial protein conformations and functions. This possibility can now beexplored by screening other fluorescence-quenching agents for possible antimicrobial activities.

Interleukin-6 is a multifunctional cytokine that has been shown to be increased in some pathological conditionsinvolving the respiratory system such as those experimentally induced in animals or spontaneously occurring in humans.Experimental data demonstrating that interleukin-6 plays a significant role in commonly occurring respiratory systeminflammatory diseases are reviewed here.Those diseases, i.e. asthma and chronic obstructive pulmonary disease, are characterised by mechanical derangements ofthe respiratory system, for the most part due to increased elastance and airway resistance. Recent findings showing thatinterleukin-6 has a causative role in determining an increase in airway resistance are reviewed.The end-inflation occlusion method was used to study the mechanical properties of the respiratory system before and afterinterleukin-6 administration. The cytokine was shown to induce significant, dose-dependent increments in both theresistive pressure dissipation due to frictional forces opposing the airflow in the airway (ohmic resistance) and theadditional resistive pressure dissipation due to the visco-elastic properties of the system, i.e. stress relaxation (visco-elasticresistance). There were no alterations in respiratory system elastance.Even when administered to healthy mammals, interleukin-6 determines a significant effect on respiratory systemresistance causing an increase in the mechanical work of breathing during inspiration. IL-6 hypothetically plays an activerole in the pathogenesis of respiratory system diseases and the mechanisms that may be involved are discussed here.

Cardiac Involvement in ANCA (+) and ANCA (-) Churg-Strauss Syndrome Evaluated by Cardiovascular Magnetic Resonance by Sophie Mavrogeni, Georgia Karabela, Elias Gialafos, Efthymios Stavropoulos, George Spiliotis, Gikas Katsifis, Genovefa Kolovou (322-327).
Introduction: The cardiovascular magnetic resonance (CMR) pattern of Churg-Strauss syndrome (CSS)includes myopericarditis, diffuse subendocardial vasculitis or myocardial infarction with or without cardiac symptoms andis usually associated with lack of antineutrophil cytoplasmic antibodies (ANCA).Aim: To correlate the CMR pattern with ANCA in CSS, compare it with healthy controls and systemic lupuserythematosus (SLE) patients and re-evaluate 2 yrs after the first CMR.Patients-Methods: 28 consecutive CSS, aged 42±7 yrs, were referred for CMR and 2 yrs re-evaluation. The CMRincluded left ventricular ejection fraction (LVEF), T2-weighted (T2-W), early (EGE) and late gadolinium enhanced(LGE) imaging. Their results were compared with 28 systemic lupus erythematosus (SLE) under remission and 28controls with normal myocardial perfusion, assessed by scintigraphy.Results: CMR revealed acute cardiac lesions in all ANCA (-) CSS with active disease and acute cardiac symptoms andonly in one asymptomatic ANCA (+) CSS, with active disease. Diffuse subendocardial fibrosis (DSF) or past myocarditiswas identified in both ANCA(+) and ANCA (-) CSS, but with higher incidence and fibrosis amount in ANCA (-) CSS(p<0.05). In comparison to SLE, both ANCA (+) and ANCA (-) CSS had higher incidence of DSF, lower incidence ofmyocarditis and no evidence of myocardial infarction, due to coronary artery disease (p<0.05). In 2 yrs CMR follow up,1/3 of CSS with DSF presented LV function deterioration and one died, although immunosuppressive treatment was givenearly after CSS diagnosis.Conclusions: Cardiac involvement either as DSF or myocarditis, can be detected in both ANCA (+) and ANCA (-) CSS,although more clinically overt in ANCA (-). DSF carries an ominous prognosis for LV function. CMR, due to itscapability to detect disease severity, before cardiac dysfunction takes place, is an excellent tool for CSS risk stratificationand treatment individualization.

Novel carrier-linked azo prodrugs of 4 and 5-aminosalicylic acids (4-ASA and 5-ASA respectively) using thesame drugs as carriers in different permutations and combinations were designed for targeting colon affected withinflammatory bowel disease (IBD). Improved hydrophilic nature of the prodrugs assisted in minimizing their absorptionin upper GIT and efficient delivery of the active drugs to colon as evidenced from their stability in aqueous buffers (pH1.2 and 7.4) and upper GIT homogenates with 68-91% release on incubation with rat cecal matter. Amongst the series,4A4AAZ (prodrug of 4-ASA with 4-ASA) at a dose of 53 mg/Kg was found to be the most promising candidate as itsubstantially alleviated the quantifying markers of colonic inflammation in TNBS-induced experimental colitis in Wistarrats. Moreover it displayed significantly lower GI toxicity (at ten times higher dose). 5-ASA- induced pancreatitis andsulfapyridine-induced adverse effects on liver that are characteristic of sulfasalazine were not observed with 4A4AAZ. Itcould be explored further as a potential candidate for IBD patients intolerant to pancreatitis induced by oral administrationof 5-ASA.

Several studies describing the “natural history” of Peyronie’s disease Chronic Inflammation ofthe Tunica Albuginea-CITA) showed that untreated patients with PD seem to have spontaneous improvement. Because ofthese articles many physicians found to have a non-therapeutic behavior in case of PD. This paper tries to define thenatural history of PD using penile dynamic duplex ultrasound evaluation in function of factors able to elicit fibrosis of thepenis. Eighty-two patients have been studied, the mean time being between PD onset and diagnosis was 9.6 ± 3.8 months,mean age was 52.6 ± 10.69. Each patient underwent to two clinical assessments for PD, with a time-lag of 18.08 ± 9.2months. Each assessment comprises: measurement of: plaque volume in cm3 (with dynamic echocolor Dopplerultrasonography), penile curvature in degrees (with Kelami method), pain (with Pain Intensity Numerical Rating Scale/PINRS)and sexual function (with IIEF15 scale). The following clinical and laboratory assessments were carried out on eachpatient: body-mass index (BMI), blood pressure measurement, blood count, serum glutamic oxaloacetic transaminase,serum glutamic pyruvic transaminase, blood sugar, glycated haemoglobin and total testosterone. We assessed whether PDplaque volume, penile deformity, pain and modify by time, in function of risk factors of fibrosis (aging, smoking habit,erectile failure, number of comorbidities, BMI, radical prostatectomy) and/or of the severity of symptoms (plaque area,penile deformity and calcifications). Qualitative-quantitative non parametric multivariate analysis has been used asstatistical test. The analysis indicated that PD symptoms increase by time in the majority of the patients, and that theincrease is not linked to the severity of symptoms, but to the risk factors for developing fibrosis, with the exception of agethat is inversely related. PD is a progressive disease, whose progression is linked to young age and to risk factors offibrosis.

Anti-Inflammatory Treatments for Chronic Diseases: A Review by Durgaprasad Laveti, Manoj Kumar, R. Hemalatha, Ramakrishna Sistla, V. G.M. Naidu, Venu Talla, Vinod Verma, Navrinder Kaur, Ravinder Nagpal (349-361).
Inflammation is viewed as one of the major causes for the development of different diseases like cancer,cardiovascular disease, diabetes, obesity, osteoporosis, rheumatoid arthritis, inflammatory bowel disease, asthma, andCNS related diseases such as depression and parkinson’s disease; and this fervent phenomenon provides space forunderstanding different inflammatory markers. Increasing evidences have elucidated the outcome of inflammatorypathways dysregulation resulting in many symptoms of chronic diseases. The detection of transcription factors such asnuclear factor kappa-B (NF-Κ B), STAT and their gene products such as COX-2, cytokines, chemokines and chemokinereceptors has laid molecular foundation for the important role of inflammation in chronic diseases in which the NF- ΚB isreported as a major mediator which makes a possible way for the development of new therapeutic approaches usingsynthetic and natural compounds that might eventually decrease the prevalence of these diseases. Even if manyinflammatory markers like TNF-α, IL-1, IL-6, IL-8 and C-reactive protein (CRP) are reported to be the major key factorswith proved role in several inflammatory diseases, IL-1 and TNF-α are the important cytokines that can induce theexpression of NF-Κ B which is the potential target in these inflammatory diseases. This review aims to explore andsummarize that how some drugs and natural compounds show their modulatory activity in inflammatory pathways andchronic inflammatory markers in these inflammatory diseases.

The association between autoimmune rheumatic diseases and obstructive sleep apnea (OSA) is complex.Systemic inflammation secondary to OSA may underlie this association. It is possible that OSA-related inflammation maytrigger the occurrence of autoimmune rheumatic disease in genetically susceptible individuals.On the other hand, autoimmune rheumatic diseases can lead to OSA or worsen preexisting OSA. Temporomandibularjoint destruction, cervical spine subluxation and brainstem compression are the factors responsible for the aboveobservation.Future studies are needed to clarify whether OSA is an independent risk factor for the development of autoimmunedisease and whether OSA management will lead to a reduction in the incidence of autoimmune disease. On the otherhand, it is important to treat autoimmune rheumatic disease promptly, to reduce the risk of complications, with OSA beingone of these.