Inflammation In Offspring Research Articles

Exposure to low doses of formaldehyde during pregnancy suppresses the development of allergic lung inflammation in offspring

Formaldehyde (FA) is an environmental and occupational pollutant, and its toxic effects on the immune system have been shown. Nevertheless, no data are available regarding the programming mechanisms after FA exposure and its repercussions for the immune systems of offspring. In this study, our objective was to investigate the effects of low-dose exposure of FA on pregnant rats and its repercussion for the development of allergic lung inflammation in offspring.Pregnant Wistar rats were assigned in 3 groups: P (rats exposed to FA (0.75ppm, 1h/day, 5days/week, for 21days)), C (rats exposed to vehicle of FA (distillated water)) and B (rats non-manipulated). After 30days of age, the offspring was sensitised with ovalbumin (OVA)-alum and challenged with aerosolized OVA (1%, 15min, 3days). After 24h the OVA challenge the parameters were evaluated.Our data showed that low-dose exposure to FA during pregnancy induced low birth weight and suppressed the development of allergic lung inflammation and tracheal hyperresponsiveness in offspring by mechanisms mediated by reduced anaphylactic antibodies synthesis, IL-6 and TNF-alpha secretion. Elevated levels of IL-10 were found. Any systemic alteration was detected in the exposed pregnant rats, although oxidative stress in the uterine environment was evident at the moment of the delivery based on elevated COX-1 expression and reduced cNOS and SOD-2 in the uterus. Therefore, we show the putative programming mechanisms induced by FA on the immune system for the first time and the mechanisms involved may be related to oxidative stress in the foetal microenvironment.

Selective organ specific inflammation in offspring harbouring microchimerism from strongly alloreactive mothers

The origins of autoimmunity are not yet understood despite significant advances in immunology. The trafficking of maternal cells to the offspring represents the very first immunological event in foetal life and is reinforced during lactation. The persistence of maternal cells in offspring's tissues and circulation has been associated with several autoimmune disorders. However a direct causal effect has never been demonstrated. Maternal T cells specifically targeting foetal insulin producing cells have been shown to generate islet inflammation without directly participating in this process. Our objective was to evaluate if alloreactive maternal cells could directly trigger a graft-versus host like reaction or indirectly influence the development of the offspring's regulatory T cells favouring autoimmunity. We adopted a breeding strategy comparing genetically identical offspring from either strongly alloreactive transgenic mothers compared to immunodeficient mothers. We detected maternal alloreactive T cells in the offspring and early signs of inflammation in small intestine of 6 weeks old offspring. Interestingly, CD4+ Foxp3+ regulatory T cell frequency was diminished in mesenteric lymph nodes from eight months old offspring born of alloreactive mothers compared to offspring of immunodeficient mothers. Our study favours a hypothesis where highly alloreactive maternal cell microchimerism indirectly predisposes offspring to autoimmunity.

Perinatal maternal administration of Lactobacillus paracasei NCC 2461 prevents allergic inflammation in a mouse model of birch pollen allergy.

BackgroundThe hygiene hypothesis implies that microbial agents including probiotic bacteria may modulate foetal/neonatal immune programming and hence offer effective strategies for primary allergy prevention; however their mechanisms of action are poorly understood. We investigated whether oral administration of Lactobacillus paracasei NCC 2461 to mothers during gestation/lactation can protect against airway inflammation in offspring in a mouse model of birch pollen allergy, and examined the immune mechanisms involved.MethodsBALB/c mice were treated daily with L. paracasei in drinking water or drinking water alone in the last week of gestation and during lactation. Their offspring were sensitized with recombinant Bet v 1, followed by aerosol challenge with birch pollen extract.ResultsMaternal exposure to L. paracasei prevented the development of airway inflammation in offspring, as demonstrated by attenuation of eosinophil influx in the lungs; reduction of IL-5 levels in bronchoalveolar lavage, and in lung and mediastinal lymph node cell cultures; and reduced peribronchial inflammatory infiltrate and mucus hypersecretion. While allergen-specific IgE and IgG antibody levels remained unchanged by the treatment, IL-4 and IL-5 production in spleen cell cultures were significantly reduced upon allergen stimulation in offspring of L. paracasei treated mice. Offspring of L. paracasei supplemented mothers had significantly reduced Bet v 1-specific as well as Concanavalin A-induced responses in spleen and mesenteric lymph node cell cultures, suggesting the modulation of both antigen-specific and mitogen-induced immune responses in offspring. These effects were associated with increased Foxp3 mRNA expression in the lungs and increased TGF-beta in serum.ConclusionOur data show that in a mouse model of birch pollen allergy, perinatal administration of L. paracasei NCC 2461 to pregnant/lactating mothers protects against the development of airway inflammation in offspring by activating regulatory pathways, likely through TLR2/4 signalling.

Prenatal allergen exposures prevent allergen‐induced sensitization and airway inflammation in young mice

Immune-modulation such as tolerance induction appears to be an upcoming concept to prevent development of atopic diseases. Pregnancy might present a critical period for preventing allergic sensitization of the progeny. We investigated the effect of maternal allergen exposures during pregnancy on allergen-induced sensitization and airway inflammation in the offspring in a murine model. BALB/c mice were exposed to aerosolized ovalbumin (OVA) three times per week from day 7 of pregnancy until delivery (day 0). Offspring were systemically sensitized by six intraperitoneal injections with OVA between postnatal days 21 and 35, prior to airway allergen challenges on days 48, 49, and 50. Analyses were performed on day 52. To examine long-lasting effects of maternal OVA exposures some offspring were sensitized between days 115 and 129; analyses took place on day 147. Compared to maternal placebo exposures, maternal OVA exposures suppressed OVA-specific IgE serum levels and inhibited development of allergen-induced airway inflammation in the OVA-sensitized offspring on both days 52 and 147. This protective effect was associated with a shift from a predominant Th2 immune response toward a predominant production of the cytokines IFN-γ and IL-10. Further, maternal OVA exposures were associated with development of CD25(+) Foxp3(+) regulatory T cells (T(regs)) in the OVA-sensitized offspring. Depletion of T(regs) or neutralization of IL-10 prior to allergen sensitization re-established OVA-induced sensitization and eosinophilic airway inflammation in the OVA-sensitized offspring. In our model, maternal allergen exposures during pregnancy prevented later allergen-mediated sensitization and airway inflammation by allergen-specific tolerance induction in the offspring.

Effect of gestational hypercholesterolemia and maternal immunization on offspring plasma eicosanoids

Maternal immunization with oxidized low-density lipoprotein prior to pregnancy prevents pathogenic in utero programming by gestational hypercholesterolemia, but it is unknown whether gestational hypercholesterolemia and maternal immunization affect similar pathways. A lipidomic approach was used for unbiased plasma eicosanoid profiling in adult offspring of immunized and nonimmunized normocholesterolemic or hypercholesterolemic rabbit mothers. Gestational hypercholesterolemia was associated with increased levels of some eicosanoids formed by the cyclooxygenase and 12-lipoxygenase pathways only (including thromboxane B2, prostaglandin [PG] F2α, PGE2, and PGD2). Immunization of hypercholesterolemic or normocholesterolemic mothers reduced 9 of 14 eicosanoids of the cyclooxygenase pathway, 21 of 23 eicosanoids of the 5- and 12-lipoxygenase pathways (eg, 5-hydroxyeicosatetraenoic acid, hepoxilin B3, 12-hydroxyeicosatetraenoic acid), 8 of 19 eicosanoids of the cytochrome P-450 pathway, and all metabolites of the nonenzymatic pathway. Maternal immunization not only counteracts in utero programming by gestational hypercholesterolemia but reduces a broad range of eicosanoid modulators of immunity and inflammation in offspring.

Simple Interventions in Middle Age May Lower Alzheimer's Risk

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessSimple Interventions in Middle Age May Lower Alzheimer's RiskJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:18 Dec 2009https://doi.org/10.1176/pn.44.24.psychnews_44_24_019AbstractAlzheimer's disease has a strong genetic component. For example, twin studies have implied that at least 60 percent of the risk of developing Alzheimer's is under genetic control. So what can middle-aged people with a parental history of Alzheimer's do to ward off the disease?Bringing high blood pressure and inflammatory markers called cytokines to heel might be one way, a new study suggests.The study was headed by Eric van Exel, M.D., Ph.D., a geriatric psychiatrist affiliated with the VU University Medical Center in Amsterdam, the Netherlands, and published in the November Archives of General Psychiatry.The researchers conducted their study on some 400 middle-aged subjects (average age 50). Half had a parental history of Alzheimer's. Each of the subjects was evaluated for the APOE-e4 gene variant that has been strongly linked to Alzheimer's; for high blood pressure, which has also been strongly linked with Alzheimer's; and for inflammatory markers in the blood called cytokines. Cytokines have been found in abundance in and around amyloid plaques in the brain, implying that they participate in the Alzheimer's neurodegenerative process. The researchers then compared the APOE-e4, blood pressure, and cytokine results for the two study groups.The APOE-e4 gene variant was present significantly more often in subjects with a parental history of Alzheimer's than in the control group—that is, in 47 percent of the former and in 21 percent of the latter. So was high blood pressure; it was present in 40 percent of subjects with a parental history of Alzheimer's, but in only 29 percent of subjects without. And significantly higher levels of inflammatory cytokines were found in the blood of the group with a parental history of Alzheimer's than in the control group. Furthermore, these results remained firm even when some possibly confounding factors such as education, stress, smoking, fat intake, and physical activity were considered.Thus, the researchers concluded that in addition to the APOE-e4 gene variant, high blood pressure and inflammatory cytokines “in middle age are early risk factors for Alzheimer's in old age.”This news may disturb middle-aged individuals with a parental history of Alzheimer's. But it could also have a silver lining—helping them avoid Alzheimer's themselves.For instance, if these individuals find that they have high blood pressure and then bring it under control, it might help keep them from developing Alzheimer's, van Exel suggested to Psychiatric News. “We feel that it is important that both doctors/psychiatrists and middle-aged first-degree relatives of subjects diagnosed with Alzheimer's should realize that prevention of high blood pressure is the first step to reduce the incidence of Alzheimer's.”Support for this position comes not just from the results that he and his group obtained but also from findings reported by French researchers in the October 24, 1998, Lancet, van Exel pointed out. The study included more than 2,000 individuals aged 60 or older with high blood pressure and no dementia. Over a two-year period, half the subjects got treatment for their high blood pressure, whereas the other half got a placebo. At the end of that time, the two groups were compared regarding the development of dementia. The group that had received medication for high blood pressure had a 50 percent lower incidence of dementia than the control group.If middle-aged persons with a parental history of Alzheimer's took a nonsteroidal anti-inflammatory drug (NSAID) to counter inflammatory cytokines in their bodies, that too might possibly help prevent or delay the development of Alzheimer's, van Exel said, although the evidence in that domain is somewhat conflicting. For example, a study reported in the May 6, 2008, Neurology suggested that the NSAID ibuprofen could protect against Alzheimer's. But a study reported in the July 2008 Archives of Neurology implied that two other NSAIDs—naproxen and celecoxib—did not possess this capability (Psychiatric News, July 4, 2008).Provided they get the funding, van Exel and his team will be following their cohort to see whether lowering high blood pressure or inflammatory cytokines can prevent Alzheimer's.The study was funded by the European Union, the International Foundation for Alzheimer Research in the Netherlands, and the U.S. National Institute on Aging.An abstract of “Vascular Factors and Markers of Inflammation in Offspring With a Parental History of Late-Onset Alzheimer Disease” is posted at <http://archpsyc.ama-assn.org/cgi/content/abstract/66/11/1263>. ISSUES NewArchived

Vascular Factors and Markers of Inflammation in Offspring With a Parental History of Late-Onset Alzheimer Disease

Alzheimer disease (AD) is a complex disorder with a strong heritable component. Amyloid pathology, vascular factors, and inflammation are postulated to be involved in its pathogenesis, but causality has not been established unequivocally. To identify heritable traits in middle age that contribute to AD. We used a proven family design, comparing middle-aged offspring with and without a parental history of AD. In such a design, the offspring under study are enriched for risk factors of AD but do not yet have the disease. The Netherlands. Two hundred six offspring of 92 families with a parental history of late-onset AD and 200 offspring of 97 families without a parental history of AD. The APOE epsilon4 genotype, vascular factors, production capacity of pro- and anti-inflammatory cytokines upon stimulation with lipopolysaccharide, and circulating markers of inflammation. All outcome measures were assessed in the offspring only and not in the parental generation. More offspring with a parental history of AD carried APOE epsilon4 than those without a parental history of the disease (47% vs 21%, P < .001). Those with a parental history of AD also had higher systolic blood pressures (P = .006), higher diastolic blood pressures (P < .001), and lower ankle brachial indices (P = .005) when compared with offspring without a family history of dementia. Production capacity of pro-inflammatory cytokines in offspring with a parental history of AD was also different, with higher levels of IL-1beta (interleukin 1beta) (P < .001), IL-1beta to IL-1ra ratio (P < .001), tumor necrosis factor alpha (P = .008), IL-6 (P = .04), and interferon gamma (P = .01). All of these positive associations were independent of APOE epsilon4 genotype. Hypertension and the expression of an innate pro-inflammatory cytokine profile in middle age are early risk factors of AD in old age. For the offspring of affected families, it provides clues for screening and preventive strategies, of which blood pressure control can be implemented directly.

Maternal consumption of fructo-oligosaccharide diminishes the severity of skin inflammation in offspring of NC/Nga mice

Strategies to manipulate the gut microbiota in infancy have been considered to prevent the development of allergic diseases later in life. We aimed to elucidate the effects of maternal dietary supplementation with a prebiotic oligosaccharide on gut microbiota and spontaneously developing atopic dermatitis-like skin lesions in the offspring of NC/Nga mice. Female NC/Nga mice were fed diets either with or without fructo-oligosaccharide supplementation during pregnancy and lactation. After weaning, offspring were fed the diets supplemented with or without fructo-oligosaccharide for 11 weeks in an air-uncontrolled conventional room. Changes in gut microbiota were assessed by denaturing gradient gel electrophoresis of the PCR-amplified 16S rRNA gene. Skin lesions were evaluated by a clinical score and scratching behaviour. Serum antibody levels were measured by ELISA, and expression levels of cytokines and chemokines in lesional tissue were evaluated by quantitative RT-PCR. Maternal supplementation with fructo-oligosaccharide modulated the gut microbiota in sucklings. Although maternal supplementation with fructo-oligosaccharide suppressed the increase in clinical skin severity score and scratching behaviour in offspring, dietary fructo-oligosaccharide after weaning was less effective. The diminution of skin lesions was accompanied by lower serum concentrations of total IgG1 and lower expression levels of TNF-alpha in the lesional tissue. These data suggest that maternal consumption of fructo-oligosaccharide diminishes the severity of atopic dermatitis-like skin lesions in the offspring of NC/Nga mice.

3B-5 Statin treatment corrects endothelial dysfunction but not markers of inflammation in offspring of protein restricted dams

3B-5 Statin treatment corrects endothelial dysfunction but not markers of inflammation in offspring of protein restricted dams

Patient reports of preventable problems and harms in primary health care.

Despite recent attention given to medical errors, little is known about the kinds and importance of medical errors in primary care. The principal aims of this study were to develop patient-focused typologies of medical errors and harms in primary care settings and to discern which medical errors and harms seem to be the most important. Thirty-eight in-depth anonymous interviews of adults from rural, suburban, and urban locales in Virginia and Ohio were conducted to solicit stories of preventable problems with primary health care that led to physical or psychological harm. Transcriptions were analyzed to identify, name, and organize the stories of errors and harms. The 38 narratives described 221 problematic incidents that predominantly involved breakdowns in the clinician-patient relationship (n = 82, 37%) and access to clinicians (n = 63, 29%). There were several reports of perceived racism. The incidents were linked to 170 reported harms, 70% of which were psychological, including anger, frustration, belittlement, and loss of relationship and trust in one's clinician. Physical harms accounted for 23% of the total and included pain, bruising, worsening medical condition, and adverse drug reactions. The errors reported by interviewed patients suggest that breakdowns in access to and relationships with clinicians may be more prominent medical errors than are technical errors in diagnosis and treatment. Patients were more likely to report being harmed psychologically and emotionally, suggesting that the current preoccupation of the patient safety movement with adverse drug events and surgical mishaps could overlook other patient priorities.