The majority of patients with severe or difficult-to-control asthma in the United States are obese. Epidemiological studies have clearly established that obese patients tend to have worse asthma control and increased hospitalizations and do not respond to standard controller therapy as well as lean patients with asthma. Less clear are the mechanistic underpinnings for the striking clinical differences between lean and obese patients with asthma. Because obesity is principally a disorder of metabolism and energy regulation, processes fundamental to the function of every cell and system within the body, it is not surprising that it affects the respiratory system; it is perhaps surprising that it has taken so long to appreciate how dysfunctional metabolism and energy regulation lead to severe airway disease. Although early investigations focused on identifying a common factor in obesity that could promote airway disease, an appreciation has emerged that the asthma of obesity is a manifestation of multiple anomalies related to obesity affecting all the different pathways that cause asthma, and likely also to de novo airway dysfunction. Consequently, all the phenotypes of asthma currently recognized in lean patients (which are profoundly modified by obesity), as well as those unique to one's obesity endotype, likely contribute to obese asthma in a particular individual. This perspective reviews what we have learned from clinical studies and animal models about the phenotypes of asthma in obesity, which show how specific aspects of obesity and altered metabolism might lead to de novo airway disease and profoundly modify existing airway disease.

/pdf/mechanisms-of-asthma-in-obesity-pleiotropic-aspects-of-23touzypsf.pdf

Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

Diet and Metabolism in the Evolution of Asthma and Obesity.

Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage : anti-inflammatory effect of cholecystokinin

NEW FINDINGS What is the central question of this study? When do alterations in pulmonary mechanics occur following chronic low-dose administration of bleomycin? What is the main finding and its importance? Remarkably, we report changes in lung mechanics as early as day 7 that corresponded to parameters determined from single-frequency forced oscillation manoeuvres and pressure-volume loops. These changes preceded substantial histological changes or changes in gene expression levels. These findings are significant to refine drug discovery in idiopathic pulmonary fibrosis, where preclinical studies using lung function parameters would enhance the translational potential of drug candidates where lung function readouts are routinely performed in the clinic. ABSTRACT Idiopathic pulmonary fibrosis (IPF) is the most widespread form of interstitial lung disease and, currently, there are only limited treatment options available. In preclinical animal models of lung fibrosis, the effectiveness of experimental therapeutics is often deemed successful via reductions in collagen deposition and expression of profibrotic genes in the lung. However, in clinical studies, improvements in lung function are primarily used to gauge the success of therapeutics directed towards IPF. Therefore, we examined whether changes in respiratory system mechanics in the early stages of an experimental model of lung fibrosis can be used to refine drug discovery approaches for IPF. C57BL/6J mice were administered bleomycin (BLM) or a vehicle control i.p. twice a week for 4 weeks. At 7, 14, 21, 28 and 33 days into the BLM treatment regimen, indices of respiratory system mechanics and pressure-volume relationships were measured. Concomitant with these measurements, histological and gene analyses relevant to lung fibrosis were performed. Alterations in respiratory system mechanics and pressure-volume relationships were observed as early as 7 days after the start of BLM administration. Changes in respiratory system mechanics preceded the appearance of histological and molecular indices of lung fibrosis. Administration of BLM leads to early changes in respiratory system mechanics that coincide with the appearance of representative histological and molecular indices of lung fibrosis. Consequently, these data suggest that dampening the early changes in respiratory system mechanics might be used to assess the effectiveness of experimental therapeutics in preclinical animal models of lung fibrosis.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/EP087322

Low-dose administration of bleomycin leads to early alterations in lung mechanics

A review of the effects of ciglitazone on the pancreatic islets of obese, hyperglycemic mice.

30 31 Atopic, obese asthmatics exhibit airway obstruction with variable degrees of eosinophilic, 32 airway inflammation. We previously reported that mice obese due to a genetic deficiency in 33 either leptin (ob/ob mice) or the long isoform of the leptin receptor (db/db mice) exhibit 34 enhanced airway obstruction in the presence of decreased numbers of bronchoalveolar lavage 35 fluid (BALF) eosinophils as compared to lean, wild-type mice following antigen (ovalbumin; 36 OVA) sensitization and challenge. To determine if the genetic modality of obesity induction 37 influences the development of OVA-induced airway obstruction and OVA-induced pulmonary 38 inflammation, we examined indices of these sequelae in mice obese due to a genetic deficiency 39 in carboxypeptidase E, an enzyme that processes pro-hormones and pro-neuropeptides involved 40 in satiety and energy expenditure (Cpe mice). Accordingly, Cpe and lean, wild-type 41 (C57BL/6) mice were sensitized to OVA and then challenged with either aerosolized phosphate42 buffered saline (PBS) or OVA. Compared to genotype-matched, OVA-sensitized and PBS43 challenged mice, OVA sensitization and challenge elicited airway obstruction and increased 44 BALF eosinophils, macrophages, neutrophils, interleukin (IL)-4, IL-13, IL-18, and chemerin. 45 However, OVA challenge enhanced airway obstruction and pulmonary inflammation in Cpe as 46 compared to wild-type mice. These results demonstrate that OVA sensitization and challenge 47 enhances airway obstruction in obese mice regardless of the genetic basis of obesity whereas the 48 degree of OVA-induced pulmonary inflammation is dependent on the genetic modality of 49 obesity induction. These results have important implications for animal models of asthma, as 50 modeling the pulmonary phenotypes for subpopulations of atopic, obese asthmatics critically 51 depends on selecting the appropriate mouse model. 52

Effect of antigen sensitization and challenge on oscillatory

Objective The objective is to assess the reasoning by families in deciding between a home vs. facility delivery and vaginal vs. caesarean. Study design The authors selected a convenience sample of 16 villages in Sathkira district in southwest Bangladesh. Evidence was drawn from detailed in-home post-delivery interviews with all mothers in these villages who delivered in 2015 or 2016. Methods Local family health workers and paramedics used a structured questionnaire that enabled gathering of relevant quantitative and qualitative evidence. Mothers' reasons for selection of delivery location and type were categorized, and regression analysis was conducted to assess significance of variables that proxy supply and demand factors. Results Among 492 completed interviews, 48% were home deliveries, 52% facility deliveries; two-thirds of facility deliveries in private clinics. Overall, sample caesarean rate is 39%, public hospital rate 53%, private clinic rate 86%. Over half of reasons for home delivery refer to pregnancy without complication or access to trusted birth attendant. Over half of reasons for facility delivery refer to medical complications allegedly precluding home delivery, or requiring home-to-facility transfer during labour for reasons not clear to the mother. The decision depends on both 'demand' factors originating with the family (proxied by family income, birth order and education levels) and 'supply' factors originating with obstetric care providers (proxied by number of antenatal visits and variation of caesarean rate by village). In a regression controlling for both demand and supply variables, the above proxy variables are all significant. Implications for nursing and health policy Bangladesh has inadequate nursing support for vaginal delivery in either home or facility. Hence, physicians frequently recommend that women deliver in a facility (usually a physician's clinic). Physicians are reluctant to hire adequate nurses to attend vaginal deliveries. Hence, families with some discretionary income are increasingly opting for a caesarean over vaginal delivery. Facility deliveries reduce incidence of obstructed labour fistula, but probably contribute to rising incidence of iatrogenic fistula. Reducing caesarean rates requires a large increase in numbers of nurses and midwives, and acceptance by physicians of a broad scope of practice for nurses/midwives in vaginal deliveries.

Why has the caesarean rate increased dramatically in Bangladesh

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Effect of antigen sensitization and challenge on oscillatory

Why has the caesarean rate increased dramatically in Bangladesh