Maternal high-fat hypercaloric diet during pregnancy results in persistent metabolic and respiratory abnormalities in offspring.

BACKGROUND: We have shown in a previous population-based study significant correlation between childhood asthma and early abnormalities of lipid and glucose metabolism. This study's specific aim was to determine whether maternal nutrition in pregnancy affects postnatal metabolic and respiratory outcomes in the offspring. METHODS: On gestation day 1, dams were switched from standard chow to either high-fat hypercaloric diet or control diet. Terminal experiments were performed on newborn and weanling offspring of dams fed the study diet during gestation and lactation, and on adult offspring maintained on the same diet as their mother. RESULTS: Pups born from high-fat hypercaloric diet (HFD) dams developed metabolic abnormalities persistent throughout development. Cytokine expression analysis of lung tissues from newborns born to HFD dams revealed a strong proinflammatory pattern. Gene expression of neurotrophic factors and receptors was upregulated in lungs of weanlings born to HFD dams, and this was associated to higher respiratory system resistance and lower compliance at baseline, as well as hyperreactivity to aerosolized methacholine. Furthermore, HFD dams delivered pups prone to develop more severe disease after respiratory syncytial virus (RSV) infection. CONCLUSION: Maternal nutrition in pregnancy is a critical determinant of airway inflammation and hyperreactivity in offspring and also increases risk for bronchiolitis independent from prepregnancy nutrition.

Comparison of Intraoperative Aminophylline Versus Furosemide in Treatment of Oliguria During Pediatric Cardiac Surgery.

OBJECTIVES: To determine if intraoperative aminophylline was superior to furosemide to prevent or attenuate postoperative cardiac surgery-associated acute kidney injury. DESIGN: Single-center, historical control, retrospective cohort study. SETTING: PICU, university-affiliated children's hospital. PATIENTS: Children with congenital heart disease in PICU who received furosemide or aminophylline to treat intraoperative oliguria. INTERVENTIONS: Intraoperative oliguria was treated either with furosemide (September 2007 to February 2012) or with aminophylline (February 2012 to June 2013). The postoperative 48 hours renal outcomes of the aminophylline group were compared with the furosemide group. The primary outcomes were acute kidney injury and renal replacement therapy use at 48 hours postoperatively. Surgical complexity was accounted for by the use of Risk Adjustment for Congenital Heart Surgery-1 score. MEASUREMENTS AND MAIN RESULTS: The study involves 69 months of observation. There were 200 cases younger than 21 years old reviewed for this study. Eighty-five cases (42.5%) developed acute kidney injury. The aminophylline group patients produced significantly more urine (mL/kg/hr) during the first 8 hours postoperatively than furosemide patients (5.1 vs 3.4 mL/kg/hr; p = 0.01). The urine output at 48 hours postoperatively was similar between the two groups. There was no difference in acute kidney injury incidence at 48 hours between the aminophylline and furosemide groups (38% vs 47%, respectively; p = 0.29). Fewer aminophylline group subjects required renal replacement therapy compared to the furosemide group subjects (n = 1 vs 7, respectively; p = 0.03). In the multi-variant predictive model, intraoperative aminophylline infusion was noted as a negative predictive factor for renal replacement therapy, but not for cardiac surgery-associated acute kidney injury. CONCLUSION: The intraoperative use of aminophylline was more effective than furosemide in reversal of oliguria in the early postoperative period. There were less renal replacement therapy-requiring acute kidney injury in children in the aminophylline group. Future prospective studies of intraoperative aminophylline to prevent cardiac surgery-associated acute kidney injury may be warranted.

Neurotrophic and neuroimmune responses to early-life Pseudomonas aeruginosa infection in rat lungs.

Early-life respiratory infection with Pseudomonas aeruginosa is common in children with cystic fibrosis or immune deficits. Although many of its clinical manifestations involve neural reflexes, little information is available on the peripheral nervous system of infected airways. This study sought to determine whether early-life infection triggers a neurogenic-mediated immunoinflammatory response, the mechanisms of this response, and its relationship with other immunoinflammatory pathways. Weanling and adult rats were inoculated with suspensions containing P. aeruginosa (PAO1) coated on alginate microspheres suspended in Tris-CaCl(2) buffer. Five days after infection, rats were injected with capsaicin to stimulate nociceptive nerves in the airway mucosa, and microvascular permeability was measured using Evans blue as a tracer. PAO1 increased neurogenic inflammation in the extra- and intrapulmonary compartments of weanlings but not in adults. The mechanism involves selective overexpression of NGF, which is critical for the local increase in microvascular permeability and for the infiltration of polymorphonuclear leukocytes into infected lung parenchyma. These effects are mediated in part by induction of downstream inflammatory cytokines and chemokines, especially IL-1beta, IL-18, and leptin. Our data suggest that neurogenic-mediated immunoinflammatory mechanisms play important roles in airway inflammation and hyperreactivity associated with P. aeruginosa when infection occurs early in life.

Effects of titanium dioxide nanoparticle exposure on neuroimmune responses in rat airways.

Exposure to ambient nanoparticles (defined as particulate matter [PM] having one dimension <100 nm) is associated with increased risk of childhood and adult asthma. Nanomaterials feature a smaller aerodynamic diameter and a higher surface area per unit mass ratio compared to fine or coarse-sized particles, resulting in greater lung deposition efficiency and an increased potential for biological interaction. The neurotrophins nerve growth factor and brain-derived neurotrophic factor are key regulatory elements of neuronal development and responsiveness of airway sensory neurons. Changes in their expression are associated with bronchoconstriction, airway hyperresponsiveness, and airway inflammation. The neurogenic-mediated control of airway responses is a key pathophysiological mechanism of childhood asthma. However, the effects of nanoparticle exposure on neurotrophin-driven airway responses and their potential role as a predisposing factor for developing asthma have not been clearly elucidated. In this study, in vivo inhalation exposure to titanium dioxide nanoparticles (12 mg/m(3); 5.6 h/d for 3 d) produced upregulation of lung neurotrophins in weanling (2-wk-old) and newborn (2-d-old) rats but not in adult (12-wk-old) animals compared to controls. This effect was associated with increased airway responsiveness and upregulation of growth-related oncogene/keratine-derived chemokine (GRO/KC; CXCL1, rat equivalent of human interleukin [IL]-8) in bronchoalveolar lavage fluid. These data show for the first time that exposure to nanoparticulate upregulates the expression of lung neurotrophins in an age-dependent fashion and that this effect is associated with airway hyperresponsiveness and inflammation. These results suggest the presence of a critical window of vulnerability in earlier stages of lung development, which may lead to a higher risk of developing asthma.

Nephron number determines susceptibility to renal mass reduction-induced CKD in Lewis and Fisher 344 rats: implications for development of experimentally induced chronic allograft nephropathy.

BACKGROUND: The Fisher 344 (F344) rat kidney transplanted to a Lewis rat recipient is a common model of chronic renal allograft nephropathy (CAN); however, CAN does not develop when the Lewis kidney is grafted into a F344 recipient. In this study we investigated whether a difference in nephron number/glomerular volume exists between the strains that could contribute to a greater susceptibility to development of kidney disease in the F344. METHODS: Separate animals, male F344 and Lewis rats, were subjected to either sham surgery or right uni-nephrectomy and infarction of 2/3 of the left kidney, to produce a 5/6 ablation/infarction injury (5/6 A/I). Serial urinary protein excretions were measured, a terminal 24-h creatinine clearance was obtained and rats were killed 11 weeks after surgery and kidneys were harvested for pathology. Glomerular volumes were measured in the sham controls of each strain. Glomerular number was counted in separate, normal rats of each strain. RESULTS: The normal F344 had approximately 30% fewer glomeruli than Lewis rats that were larger in volume. The sham F344 had similar creatinine clearance and glomerular structure to the Lewis shams, although BP and urine protein excretion were higher. After 5/6 A/I the F344 developed more severe proteinuria and structural kidney damage. When factored for kidney weight, the F344 rats exhibited a greater compensatory hyperfiltration in response to 5/6 A/I, compared to Lewis. CONCLUSIONS: The F344 strain is more vulnerable to development of progressive kidney damage due to 5/6 A/I, compared to the Lewis. This is likely due to the lower nephron number/greater glomerular volume of the F344 that may also account for the greater susceptibility to CAN exhibited by this strain.

Importance of android/gynoid fat ratio in predicting metabolic and cardiovascular disease risk in normal weight as well as overweight and obese children.

Numerous studies have shown that android or truncal obesity is associated with a risk for metabolic and cardiovascular disease, yet there is evidence that gynoid fat distribution may be protective. However, these studies have focused on adults and obese children. The purpose of our study was to determine if the android/gynoid fat ratio is positively correlated with insulin resistance, HOMA2-IR, and dislipidemia in a child sample of varying body sizes. In 7-13-year-old children with BMI percentiles ranging from 0.1 to 99.6, the android/gynoid ratio was closely associated with insulin resistance and combined LDL + VLDL-cholesterol. When separated by sex, it became clear that these relationships were stronger in boys than in girls. Subjects were stratified into BMI percentile based tertiles. For boys, the android/gynoid ratio was significantly related to insulin resistance regardless of BMI tertile with and LDL + VLDL in tertiles 1 and 3. For girls, only LDL + VLDL showed any significance with android/gynoid ratio and only in tertile 2. We conclude that the android/gynoid fat ratio is closely associated with insulin resistance and LDL + VLDL-, "bad," cholesterol in normal weight boys and may provide a measurement of metabolic and cardiovascular disease risk in that population.

Vertical transmission of respiratory syncytial virus modulates pre- and postnatal innervation and reactivity of rat airways.

BACKGROUND: Environmental exposure to respiratory syncytial virus (RSV) is a leading cause of respiratory infections in infants, but it remains unknown whether this infection is transmitted transplacentally from the lungs of infected mothers to the offspring. We sought to test the hypothesis that RSV travels from the respiratory tract during pregnancy, crosses the placenta to the fetus, persists in the lung tissues of the offspring, and modulates pre- and postnatal expression of growth factors, thereby predisposing to airway hyperreactivity. METHODOLOGY: Pregnant rats were inoculated intratracheally at midterm using recombinant RSV expressing red fluorescent protein (RFP). Viral RNA was amplified by RT-PCR and confirmed by sequencing. RFP expression was analyzed by flow cytometry and viral culture. Developmental and pathophysiologic implications of prenatal infection were determined by analyzing the expression of genes encoding critical growth factors, particularly neurotrophic factors and receptors. We also measured the expression of key neurotransmitters and postnatal bronchial reactivity in vertically infected lungs, and assessed their dependence on neurotrophic signaling using selective biological or chemical inhibition. PRINCIPAL FINDINGS: RSV genome was found in 30% of fetuses, as well as in the lungs of 40% of newborns and 25% of adults. RFP expression was also shown by flow cytometry and replicating virus was cultured from exposed fetuses. Nerve growth factor and its TrkA receptor were upregulated in RSV- infected fetal lungs and co-localized with increased cholinergic innervation. Acetylcholine expression and smooth muscle response to cholinergic stimulation increased in lungs exposed to RSV in utero and reinfected after birth, and blocking TrkA signaling inhibited both effects. CONCLUSIONS/SIGNIFICANCE: Our data show transplacental transmission of RSV from mother to offspring and persistence of vertically transmitted virus in lungs after birth. Exposure to RSV in utero is followed by dysregulation of neurotrophic pathways predisposing to postnatal airway hyperreactivity upon reinfection with the virus.

The role of neurotrophins in inflammation and allergy.

Allergic inflammation is the result of a specific pattern of cellular and humoral responses leading to the activation of the innate and adaptive immune system which, in turn, results in physiological and structural changes affecting target tissues such as the airways and the skin. Eosinophils activation and production of soluble mediators such as IgE antibodies is a pivotal feature in the pathophysiology of allergic diseases. In the past few years, however, convincing evidence has shown that neurons and other neurosensory structures are not only a target of the inflammatory process but also participate in the regulation of immune responses by actively releasing soluble mediators. The main products of these activated sensory neurons are a family of protein growth factors called neurotrophins. They were first isolated in the central nervous system and identified as important factors for the survival and differentiation of neurons during fetal and post-natal development as well as neuronal maintenance later in life. Four members of this family have been identified and well defined: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5). Neurotrophins play a critical role in the bidirectional signaling mechanisms between immune cells and the neurosensory network structures in the airways and the skin. Pruritus and airway hyperresponsiveness (AHR), two major features of atopic dermatitis and asthma, respectively, are associated with the disruption of the neurosensory network activities. In this review we provide a comprehensive description of the neuroimmune interactions underlying the pathophysiological mechanisms of allergic and inflammatory diseases.

NGF is an essential survival factor for bronchial epithelial cells during respiratory syncytial virus infection.

BACKGROUND: Overall expression of neurotrophins in the respiratory tract is upregulated in infants infected by the respiratory syncytial virus (RSV), but it is unclear where (structural vs. inflammatory cells, upper vs. lower airways) and why, these changes occur. We analyzed systematically the expression of neurotrophic factors and receptors following RSV infection of human nasal, tracheal, and bronchial epithelial cells, and tested the hypothesis that neurotrophins work as innate survival factors for infected respiratory epithelia. METHODOLOGY: Expression of neurotrophic factors (nerve growth factor, NGF; brain-derived neurotrophic factor, BDNF) and receptors (trkA, trkB, p75) was analyzed at the protein level by immunofluorescence and flow cytometry and at the mRNA level by real-time PCR. Targeted siRNA was utilized to blunt NGF expression, and its effect on virus-induced apoptosis/necrosis was evaluated by flow cytometry following annexin V/7-AAD staining. PRINCIPAL FINDINGS: RSV infection was more efficient in cells from more distal (bronchial) vs. more proximal origin. In bronchial cells, RSV infection induced transcript and protein overexpression of NGF and its high-affinity receptor trkA, with concomitant downregulation of the low-affinity p75(NTR). In contrast, tracheal cells exhibited an increase in BDNF, trkA and trkB, and nasal cells increased only trkA. RSV-infected bronchial cells transfected with NGF-specific siRNA exhibited decreased trkA and increased p75(NTR) expression. Furthermore, the survival of bronchial epithelial cells was dramatically decreased when their endogenous NGF supply was depleted prior to RSV infection. CONCLUSIONS/SIGNIFICANCE: RSV infection of the distal airway epithelium, but not of the more proximal sections, results in overexpression of NGF and its trkA receptor, while the other p75(NTR) receptor is markedly downregulated. This pattern of neurotrophin expression confers protection against virus-induced apoptosis, and its inhibition amplifies programmed cell death in the infected bronchial epithelium. Thus, pharmacologic modulation of NGF expression may offer a promising new approach for management of common respiratory infections.