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author:("Jain, deepak")
1.  Large uterus: what is the limit for a laparoscopic approach? 
Autopsy & Case Reports  2016;6(1):51-56.
Hysterectomy is the most common surgical gynecologic procedure, which is frequently related to the treatment of leiomyoma. The laparoscopic hysterectomy is associated with a shorter hospital stay, fewer infection rates, and a faster return to daily activities. Most gynecologists do not recommend a hysterectomy via the vagina or a laparoscopic-assisted vaginal hysterectomy (LAVH) in the case of a uterus weighing more than 300 g. This case report presents the case of an LAVH undertaken in a 43-year-old patient with a uterus weighing 2,800 g. There are no definite guidelines concerning the procedure for a large uterus, and the literature is vague regarding the best surgical procedure for these cases. The size of the uterus does not seem to be an absolute contraindication for endoscopic surgery. This procedure relies entirely on the surgeon's ability.
PMCID: PMC4880435  PMID: 27284542
Hysterectomy; Vaginal; Uterus; Leiomyoma
2.  Health literacy in kidney disease: Review of the literature and implications for clinical practice 
World Journal of Nephrology  2016;5(2):147-151.
Health literacy is the capacity of an individual to understand information related to a disease in order to make an informed decision. In patients with kidney diseases, studies have reported increasing impact of limited health literacy on health outcomes. Our paper discusses current literature on health literacy in kidney diseases.
PMCID: PMC4777785  PMID: 26981438
Health literacy; Kidney diseases; Rapid estimate of adult literacy in medicine; Hemodialysis; Peritoneal dialysis; Chronic kidney disease
4.  Immunostimulatory Defective Viral Genomes from Respiratory Syncytial Virus Promote a Strong Innate Antiviral Response during Infection in Mice and Humans 
PLoS Pathogens  2015;11(9):e1005122.
Human respiratory syncytial virus (RSV) is a major cause of severe respiratory illness in children and susceptible adults. RSV blocks the development of the innate antiviral immune response and can grow to high titers in the respiratory tract. Here we demonstrate that immunostimulatory defective viral genomes (iDVGs) that are naturally generated during RSV replication are strong inducers of the innate antiviral response to RSV in mice and humans. In mice, RSV iDVGs stimulated the expression of antiviral genes, restricted viral replication, and prevented weight loss and lung inflammation. In human cells, the antiviral response to RSV iDVGs was dominated by the expression of IFN-λ1 over IFN-β and was driven by rapid intranuclear accumulation of the transcription factor IRF1. RSV iDVGs were detected in respiratory secretions of hospitalized patients, and their amount positively correlated with the level of expression of antiviral genes in the samples. Infection of explanted human lung tissue from different donors revealed that most humans can respond to RSV iDVGs and that the rate of accumulation of iDVGs during infection directly correlates with the quality of the antiviral response. Taken together, our data establish iDVGs as primary triggers of robust antiviral responses to RSV and provide the first evidence for an important biological role for naturally occurring iDVGs during a paramyxovirus infection in humans.
Author Summary
Respiratory syncytial virus is a major cause of chronic lung damage, asthma exacerbations, and hospitalizations of infants, elders, and high-risk adults. Currently, there is no effective vaccine or treatment available to protect the general population from RSV infection. Here, we demonstrate that defective forms of RSV genomes naturally generated during infection effectively stimulate the antiviral response in vitro and in vivo. In human cells, RSV iDVGs trigger the antiviral response through a mechanism characterized by the potent activation of the transcription factor IRF1 and a dominant expression of the type III IFN gene IFNL1 (IFN-λ1). This study establishes for the first time that naturally occurring iDVGs trigger robust host antiviral responses to RSV in mice and humans and reveals new opportunities to potentiate the host response to RSV infection and minimize viral-induced pathology.
PMCID: PMC4559413  PMID: 26336095
5.  Incidental Findings on Cone Beam Computed Tomography and Reasons for Referral by Dental Practitioners in Indore City (M.P) 
Introduction: Cone beam computed tomography is a new diagnostic innovation to dental imaging. Despite the use of CBCT in oral and maxillofacial imaging, reports on its use either by individual practitioners or referral patterns to CBCT centers is lacking. Hence, a study was conducted to determine incidental findings on CBCT and reasons for referral by dental practitioners in Indore city.
Materials and Methods: A retrospective analysis of 795 records that were referred for CBCT imaging at Institutional and Oracal CBCT Centre, Indore was undertaken. Referrals from both within and outside institution, as well as from private practitioners were considered. The reason for CBCT referral, provision diagnosis, final diagnosis and any incidental diagnosis were recorded.
Results: This retrospective chart audit revealed that 56.7 % were male and 43.3% were females. Greatest source of patients was referred by oral surgeons (21.9%) followed by oral and maxillofacial radiologist (14.2%) and prosthodontist (9.3%). The most common reason for referral was for implant analysis (24.2%) and the most common incidental finding diagnosed by CBCT was oral malignancies.
Conclusion: In Institutional set-up, CBCT referrals were mostly for the reason of planning implant placement followed by trauma whereas private practitioners used CBCT mostly for implant placement followed by impaction. CBCT was being utilized more by Oral surgeons in private sector whereas it in an Institutional setup majority of referrals from Department of Oral Diagnosis and Radiology. Findings that were most commonly diagnosed incidentally on CBCT were Orofacial malignancies followed maxillary sinus pathologies.
PMCID: PMC4378801  PMID: 25859519
CBCT; Referral pattern; Incidental finding
6.  Deficiency of Melanoma Differentiation–associated Protein 5 Results in Exacerbated Chronic Postviral Lung Inflammation 
Rationale: Respiratory viral infections can result in the establishment of chronic lung diseases. Understanding the early innate immune mechanisms that participate in the development of chronic postviral lung disease may reveal new targets for therapeutic intervention. The intracellular viral sensor protein melanoma differentiation–associated protein 5 (MDA5) sustains the acute immune response to Sendai virus, a mouse pathogen that causes chronic lung inflammation, but its role in the development of postviral chronic lung disease is unknown.
Objectives: To establish the role of MDA5 in the development of chronic lung disease.
Methods: MDA5-deficient or control mice were infected with Sendai virus. The acute inflammatory response was evaluated by profiling chemokine and cytokine expression and by characterizing the composition of the cellular infiltrate. The impact of MDA5 on chronic lung pathology and function was evaluated through histological studies, degree of oxygen saturation, and responsiveness to carbachol.
Measurements and Main Results: MDA5 deficiency resulted in normal virus replication and in a distinct profile of chemokines and cytokines that associated with acute lung neutropenia and enhanced accumulation of alternatively activated macrophages. Diminished expression of neutrophil-recruiting chemokines was also observed in cells infected with influenza virus, suggesting a key role of MDA5 in driving the early accumulation of neutrophils at the infection site. The biased acute inflammatory response of MDA5-deficient mice led to an enhanced chronic lung inflammation, epithelial cell hyperplasia, airway hyperreactivity, and diminished blood oxygen saturation.
Conclusions: MDA5 modulates the development of chronic lung inflammation by regulating the early inflammatory response in the lung.
PMCID: PMC3977719  PMID: 24417465
respiratory virus; chronic lung disease; innate immunity; paramyxovirus
7.  Oral Health Status and Oromucosal Lesions in Patients Living with HIV/AIDS in India: A Comparative Study 
AIDS Research and Treatment  2014;2014:480247.
Oral health status of HIV positive individuals is in poor condition which may be a sequela of variety of factors. This study was aimed at assessing and comparing the oral health status and oromucosal lesions between HIV positive and negative individuals in India. A total of 126 HIV positive and 532 HIV negative individuals were recruited for the study. Oral health status and oromucosal lesions were recorded using WHO oral health assessment form (1997). Data was analyzed using chi-square and independent sample student's t test. Majority (85.7%) of people suffering from HIV belonged to lower socioeconomic status. The mean for DMFT score was found to be significantly higher in HIV positive individuals (12.83 ± 9.6) as compared to HIV negative individuals (8.34 ± 7.6) (P value < 0.0001). Nearly 75% of HIV positive individuals showed oromucosal lesions with candidiasis (36%) being the most common. Nearly 50% of HIV positive individuals had community periodontal index (CPI) and loss of attachment (LOA) score >2. In conclusion HIV positive individuals have poor oral health status and poor periodontal status compared to control group. Effective policies need to be drafted to take care of the oral health of this high risk group.
PMCID: PMC4158162  PMID: 25215229
8.  Effect of Body Mass Index on Pregnancy Outcomes in Nulliparous Women Delivering Singleton Babies: Observational Study 
To find out the effect of increasing body mass index (BMI) on pregnancy outcomes in nulliparous women delivering singleton babies.
This was a hospital-based observation study, based on 300 nulliparous women delivering singleton babies in June 2009—Sept. 2010. Women were categorized into three groups. Underweight (BMI < 20 kg/m2), normal (BMI 20–24.9 kg/m2), overweight (BMI 25–29.9 kg/m2), and obese (BMI > 30 kg/m2) obstetric and perinatal outcomes were compared by univariate and multivariate analysis.
Maximum patients who underwent LSCS were having BMI > 30 kg/m2 [OR 9.558 (95 % CI 5.82–17.27)]. As compared to women of normal BMI (20–24.9 kg/m2), morbidly obese women faced the higher risk of PIH [OR 8.045 (95 % CI 3.875–16.781)]. Obese women were more likely to have post partum hemorrhage [OR 5.11 (95 % CI 1.76–14.79)] compared with women of normal BMI. Birth weight <2,500 g was more common in women with BMI < 25 kg/m2 (21.21 %), while highest incidence of birth weight >4,000 g (14.29 %) is seen in women of the obese group.
Increasing BMI is associated with increased incidence of cesarean delivery, PIH, post partum hemorrhage, and macrosomic babies.
PMCID: PMC3500949  PMID: 23904704
Body mass index; PIH; LSCS; PPH; Birth weight
9.  Imbalance of mitochondrial-nuclear cross talk in isocyanate mediated pulmonary endothelial cell dysfunction☆ 
Redox Biology  2013;1(1):163-171.
Mechanistic investigations coupled with epidemiology, case-control, cohort and observational studies have increasingly linked isocyanate exposure (both chronic and acute) with pulmonary morbidity and mortality. Though ascribed for impairment in endothelial cell function, molecular mechanisms of these significant adverse pulmonary outcomes remains poorly understood. As preliminary studies conducted in past have failed to demonstrate a cause-effect relationship between isocyanate toxicity and compromised pulmonary endothelial cell function, we hypothesized that direct exposure to isocyanate may disrupt endothelial structural lining, resulting in cellular damage. Based on this premise, we comprehensively evaluated the molecular repercussions of methyl isocyanate (MIC) exposure on human pulmonary arterial endothelial cells (HPAE-26). We examined MIC-induced mitochondrial oxidative stress, pro-inflammatory cytokine response, oxidative DNA damage response and apoptotic index. Our results demonstrate that exposure to MIC, augment mitochondrial reactive oxygen species production, depletion in antioxidant defense enzymes, elevated pro-inflammatory cytokine response and induced endothelial cell apoptosis via affecting the balance of mitochondrial-nuclear cross talk. We herein delineate the first and direct molecular cascade of isocyanate-induced pulmonary endothelial cell dysfunction. The results of our study might portray a connective link between associated respiratory morbidities with isocyanate exposure, and indeed facilitate to discern the exposure-phenotype relationship in observed deficits of pulmonary endothelial cell function. Further, understanding of inter- and intra-cellular signaling pathways involved in isocyanate-induced endothelial damage would not only aid in biomarker identification but also provide potential new avenues to target specific therapeutic interventions.
Graphical abstract
► Pulmonary endothelial cells accomplish a vast variety of specialized functions. ► A balance in mitochondrial-nuclear cross talk is essential for endothelial integrity. ► Methyl isocyanate impairs redox balance in endothelial milieu. ► We profess a corollary between respiratory morbidities and methyl isocyanate exposure.
PMCID: PMC3757684  PMID: 24024149
Mitochondrial oxidative stress; Endothelial cell apoptosis; Pulmonary toxicity; Occupational health; Environmental medicine
10.  Granulocyte Colony-Stimulating Factor Protects Mice during Respiratory Virus Infections 
PLoS ONE  2012;7(5):e37334.
A burst in the production of pro-inflammatory molecules characterizes the beginning of the host response to infection. Cytokines, chemokines, and growth factors work in concert to control pathogen replication and activate innate and adaptive immune responses. Granulocyte colony-stimulating factor (G-CSF) mobilizes and activates hematopoietic cells from the bone marrow, and it has been shown to mediate the generation of effective immunity against bacterial and fungal infections. G-CSF is produced at high levels in the lungs during infection with influenza and parainfluenza viruses, but its role during these infections is unknown. Here we show that during infection of mice with a non-lethal dose of influenza or Sendai virus, G-CSF promotes the accumulation of activated Ly6G+ granulocytes that control the extent of the lung pro-inflammatory response. Remarkably, these G-CSF-mediated effects facilitate viral clearance and sustain mouse survival.
PMCID: PMC3353936  PMID: 22615983
11.  Factorial design-based development of measlamine microspheres for colonic delivery 
Biomatter  2011;1(2):182-188.
For treating colonic diseases, conventional oral drug delivery systems are not effective, as they fail to reach the appropriate site of action. Thus, there is a need to develop effective and safe therapy for the treatment of colonic disorders. The aim of the present study was to design a colon-specific delivery system for an anti-inflammatory drug, mesalamine, with minimal degradation and optimum delivery of the drug with relatively higher local concentration, which may provide more effective therapy for inflammatory bowel disease including Crohn disease and ulcerative colitis. Factorial designs (four factors and two levels) for eudragit S-100 (pH-dependent polymer)-coated, pectin (natural polysaccharides)-based microspheres of mesalamine were constructed and conducted in a fully randomized manner to study all possible combinations. Based on the desirability function formulation, F14 was found to be the best formulation. The overall desirability coefficient of formulation F14 was found to be 0.825. The formulation F14 was subjected to in vitro release studies, and the results were evaluated kinetically and statistically. The microspheres started releasing the drug at the beginning of 7th hour, which corresponds to the arrival time at proximal colon. The cumulative percent drug release for formulation F14 at the end of 16 h was found to be 98%. The release kinetics showed that the release followed the Higuchi model, and the main mechanism of drug release was diffusion. The study presents a new approach for colon-specific drug delivery.
PMCID: PMC3549889  PMID: 23507747
Eudragit S-100; colonic delivery; diffusion; microspheres; pectin
12.  Recent technologies in pulsatile drug delivery systems 
Biomatter  2011;1(1):57-65.
Pulsatile drug delivery systems (PDDS) have attracted attraction because of their multiple benefits over conventional dosage forms. They deliver the drug at the right time, at the right site of action and in the right amount, which provides more benefit than conventional dosages and increased patient compliance. These systems are designed according to the circadian rhythm of the body, and the drug is released rapidly and completely as a pulse after a lag time. These products follow the sigmoid release profile characterized by a time period. These systems are beneficial for drugs with chronopharmacological behavior, where nocturnal dosing is required, and for drugs that show the first-pass effect. This review covers methods and marketed technologies that have been developed to achieve pulsatile delivery. Marketed technologies, such as PulsincapTM, Diffucaps®, CODAS®, OROS® and PULSYSTM, follow the above mechanism to render a sigmoidal drug release profile. Diseases wherein PDDS are promising include asthma, peptic ulcers, cardiovascular ailments, arthritis and attention deficit syndrome in children and hypercholesterolemia. Pulsatile drug delivery systems have the potential to bring new developments in the therapy of many diseases.
PMCID: PMC3548250  PMID: 23507727
capsular system; pulsatile drug delivery system; pulse; rupturable coating
13.  Nebivolol Attenuates Maladaptive Proximal Tubule Remodeling in Transgenic Rats 
American Journal of Nephrology  2010;31(3):262-272.
The impact of nebivolol therapy on the renal proximal tubular cell (PTC) structure and function was investigated in a transgenic (TG) rodent model of hypertension and the cardiometabolic syndrome. The TG Ren2 rat develops nephropathy with proteinuria, increased renal angiotensin II levels and oxidative stress, and PTC remodeling. Nebivolol, a β1-antagonist, has recently been shown to reduce albuminuria, in part, through reductions in renal oxidative stress. Accordingly, we hypothesized that nebivolol therapy would attenuate PTC damage and tubulointerstitial fibrosis.
Young Ren2 (R2-N) and SD (SD-N) rats were treated with nebivolol (10 mg/kg/day) or vehicle (R2-C; SD-C) for 3 weeks. PTC structure and function were tested using transmission electron microscopy and functional measurements.
Nebivolol treatment decreased urinary N-acetyl-β-D-glucosaminidase, tubulointerstitial ultrastructural remodeling and fibrosis, NADPH oxidase activity, 3-nitrotyrosine levels, and increased megalin and lysosomal-associated membrane protein-2 immunostaining in PTCs. Ultrastructural abnormalities that were improved with therapy included altered canalicular structure, reduced endosomes/lysosomes and PTC vacuoles, basement membrane thickening, and mitochondrial remodeling/fragmentation.
These observations support the notion that nebivolol may improve PTC reabsorption of albumin and other glomerular filtered small molecular weight proteins in association with the attenuation of oxidative stress, tubulointerstitial injury and fibrosis in this rat model of metabolic kidney disease.
PMCID: PMC2914375  PMID: 20110666
NADPH oxidase; Proximal tubule cell; Megalin
14.  Design, Characterization, and Evaluation of Meloxicam Gel Prepared by Suspension and Solution Polymerization Using Solubility Parameter as the Basis for Development 
AAPS PharmSciTech  2010;11(1):133-142.
Meloxicam gel was designed based on the matching of the solubility parameter (δ) of the drug with that of the polymer and subsequently with skin for improved dermal delivery of meloxicam. The δ of meloxicam (11.48 (cal/cm3)0.5) determined by solubility measurement was matched statistically to the solubility parameter of monomers, n-vinyl-2-pyrrolidone, polyvinyl alcohol (PVA), hydroxyl ethyl methacrylate, ethylene glycol methacrylate (EGMA) determined by intrinsic viscosity measurement. Consequently gels were formulated by polymerization in selected solvent blend of water/ethyl acetate (20:80) in which the drug showed maximum solubility. Thus, F1–F16 formulations designed were evaluated for physicochemical properties, textural analysis, and in vitro drug release. On the basis of optimum characteristics, F2 (PVA, δ = 16.96 (cal/cm3)0.5) and F8 (EGMA, δ = 18.35 (cal/cm3)0.5) formulated by suspension polymerization were selected and subjected to skin irritation and topical anti-inflammatory studies. The formulation F8 demonstrated significant (p < 0.05) of anti-inflammatory activity in comparison to marketed piroxicam gel and was free from irritation.
PMCID: PMC2850456  PMID: 20077041
anti-inflammatory activity; hydrogel; meloxicam; physicochemical evaluation; solubility parameter
15.  Expression and activation of the oxytocin receptor in airway smooth muscle cells: Regulation by TNFα and IL-13 
Respiratory Research  2010;11(1):104.
During pregnancy asthma may remain stable, improve or worsen. The factors underlying the deleterious effect of pregnancy on asthma remain unknown. Oxytocin is a neurohypophyseal protein that regulates a number of central and peripheral responses such as uterine contractions and milk ejection. Additional evidence suggests that oxytocin regulates inflammatory processes in other tissues given the ubiquitous expression of the oxytocin receptor. The purpose of this study was to define the role of oxytocin in modulating human airway smooth muscle (HASMCs) function in the presence and absence of IL-13 and TNFα, cytokines known to be important in asthma.
Expression of oxytocin receptor in cultured HASMCs was performed by real time PCR and flow cytomery assays. Responses to oxytocin was assessed by fluorimetry to detect calcium signals while isolated tracheal rings and precision cut lung slices (PCLS) were used to measure contractile responses. Finally, ELISA was used to compare oxytocin levels in the bronchoalveloar lavage (BAL) samples from healthy subjects and those with asthma.
PCR analysis demonstrates that OXTR is expressed in HASMCs under basal conditions and that both interleukin (IL)-13 and tumor necrosis factor (TNFα) stimulate a time-dependent increase in OXTR expression at 6 and 18 hr. Additionally, oxytocin increases cytosolic calcium levels in fura-2-loaded HASMCs that were enhanced in cells treated for 24 hr with IL-13. Interestingly, TNFα had little effect on oxytocin-induced calcium response despite increasing receptor expression. Using isolated murine tracheal rings and PCLS, oxytocin also promoted force generation and airway narrowing. Further, oxytocin levels are detectable in bronchoalveolar lavage (BAL) fluid derived from healthy subjects as well as from those with asthma.
Taken together, we show that cytokines modulate the expression of functional oxytocin receptors in HASMCs suggesting a potential role for inflammation-induced changes in oxytocin receptor signaling in the regulation of airway hyper-responsiveness in asthma.
PMCID: PMC2922094  PMID: 20670427
16.  Post-Transcriptional Regulation of Urokinase-type Plasminogen Activator Receptor Expression in Lipopolysaccharide-induced Acute Lung Injury 
Rationale: Urokinase-type plasminogen activator (uPA) receptor (uPAR) is required for the recruitment of neutrophils in response to infection. uPA induces its own expression in lung epithelial cells, which involves its interaction with cell surface uPAR. Regulation of uPAR expression is therefore crucial for uPA-mediated signaling in infectious acute lung injury (ALI).
Objectives: To determine the role of uPA in uPAR expression during ALI caused by sepsis.
Methods: We used Western blot, Northern blot, Northwestern assay, and immunohistochemistry. Phosphate-buffered saline– and lipopolysaccharide (LPS)-treated wild-type and uPA−/− mice were used.
Measurements and Main Results: Biological activities of uPA, including proteolysis, cell adhesion, migration, proliferation, and differentiation, are dependent on its association with uPAR. Bacterial endotoxin (LPS) is a major cause of pulmonary dysfunction and infection-associated mortality. The present study shows that LPS induces uPAR expression both in vitro and in vivo, and that the mechanism involves post-transcriptional stabilization of uPAR mRNA by reciprocal interaction of phosphoglycerate kinase (PGK) and heterogeneous nuclear ribonucleoprotein C (hnRNPC) with uPAR mRNA coding region and 3′ untranslated region determinants, respectively. The process involves tyrosine phosphorylation of PGK and hnRNPC. uPA−/− mice failed to induce uPAR expression after LPS treatment. In these mice, LPS treatment failed to alter the binding of PGK and hnRNPC protein with uPAR mRNA due to lack of tyrosine phosphorylation.
Conclusions: Our study shows that induction of LPS-mediated uPAR expression is mediated through tyrosine phosphorylation of PGK and hnRNPC. This involves expression of uPA as an obligate intermediary.
PMCID: PMC2643078  PMID: 19029002
LPS; urokinase-type plasminogen activator; urokinase-type plasminogen activator receptor; tyrosine phosphorylation
17.  Surfactant Protein D Protects against Acute Hyperoxic Lung Injury 
Rationale: Surfactant protein D (SP-D) is a member of the collectin family of soluble, innate, host defense molecules with demonstrated immunomodulatory properties in vitro. Constitutive absence of SP-D in mice is associated with lung inflammation, alteration in surfactant lipid homeostasis, and increased oxidative-nitrative stress.
Objectives: To test the hypothesis that SP-D would protect against acute lung injury from hyperoxia in vivo.
Methods: Transgenic mice overexpressing rat SP-D constitutively (SP-D OE) or conditionally via regulation with doxycycline (SP-D Dox-on) were subjected to continuous hyperoxic challenge for up to 14 days.
Measurements and Main Results: Compared with littermate control mice (wild-type [WT]), SP-D OE mice exposed to 80% O2 demonstrated substantially increased survival accompanied by significant reductions in wet to dry lung ratios and bronchoalveolar lavage (BAL) protein. Although SP-D OE and WT mice exhibited a twofold increase in total BAL cells and neutrophilia in response to hyperoxia, the SP-D OE group had lower levels of BAL proinflammatory cytokines and chemokines, including IL-6, tumor necrosis factor-α, and monocyte chemotactic protein-1; increased mRNA levels of the transcription factor NF-E2 related factor-2 (NRF-2) and phase 2 antioxidants hemoxygenase-1 (HO-1), glutathione peroxidase-2 (GPx-2) and NAD(P)H quinone oxidoreductase-1 (Nqo-1); and decreases in lung tissue thiobarbituric acid–reactive substances. As proof of principle, the protective role of SP-D on hyperoxic injury was confirmed as SP-D Dox-on mice exposed to 85% O2 demonstrated increased mortality upon withdrawal of doxycycline.
Conclusions: Local expression of SP-D protects against hyperoxic lung injury through modulation of proinflammatory cytokines and antioxidant enzymatic scavenger systems.
PMCID: PMC2566792  PMID: 18635887
innate immunity; inflammation; collectin; antioxidants; oxidative stress
18.  Essential role of IFNβ and CD38 in TNFα-induced airway smooth muscle hyper-responsiveness 
Immunobiology  2008;213(6):499-509.
We recently identified autocrine interferon (IFN)β as a novel mechanism mediating tumor necrosis factor (TNF)α-induced expression of inflammatory genes in airway smooth muscle (ASM) cells, including CD38, known to regulate calcium signaling. Here, we investigated the putative involvement of IFNβ in regulating TNFα-induced airway hyper-responsiveness (AHR), a defining feature of asthma. Using our pharmacodynamic model to assess ex vivo AHR isolated murine tracheal rings, we found that TNFα-induced enhanced contractile responses to carbachol and bradykinin was abrogated by neutralizing anti-IFNβ antibody or in tracheal rings deficient in CD38. In cultured human ASM cells, where CD38 has been involved in TNFα-induced enhanced calcium signals to carbachol and bradykinin, we found that neutralizing anti-IFNβ prevented TNFα enhancing action only on carbachol responses but not to that induced by bradykinin. In a well-characterized model of allergic asthma (mice sensitized and challenged with Aspergillus fumigatus (Af)), we found heightened expression of both IFNβ and CD38 in the airways. Furthermore, allergen-associated AHR to methacholine, assessed by lung resistance and dynamic compliance, was completely suppressed in CD38-deficient mice, despite the preservation of airway inflammation. These data provide the first evidence that ASM-derived IFNβ and CD38 may play a significant role in the development of TNFα-associated AHR.
PMCID: PMC2587232  PMID: 18514752
Allergic asthma; Cytokine; Airway smooth muscle; Inflammation; Calcium signaling; Hypercontractility

Results 1-18 (18)