Stress and atopic disorders
2005; Elsevier BV; Volume: 116; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2005.09.050
ISSN1097-6825
Autores Tópico(s)Neuroendocrine regulation and behavior
ResumoEvidence linking psychological stress to the expression of asthma and atopy continues to grow. Examining the underlying molecular mechanisms linking stress to asthma and other allergic phenomena is an active area of research. Evidence is reviewed for the influence of stress on neuroimmunoregulation and oxidative stress pathways, which, in turn, may affect biological hypersensitivity to environmental stimuli characteristic of atopic disorders. Critical periods of development, including in utero environment, are underscored. The role of genetics and gene-by-environment interactions is also discussed. Evidence linking psychological stress to the expression of asthma and atopy continues to grow. Examining the underlying molecular mechanisms linking stress to asthma and other allergic phenomena is an active area of research. Evidence is reviewed for the influence of stress on neuroimmunoregulation and oxidative stress pathways, which, in turn, may affect biological hypersensitivity to environmental stimuli characteristic of atopic disorders. Critical periods of development, including in utero environment, are underscored. The role of genetics and gene-by-environment interactions is also discussed. Asthma and other allergic diseases have long been considered psychosomatic disorders. Indeed, before we better understood the underlying inflammatory basis of asthma, it was among the disorders believed to be purely psychogenic in origin, commonly referred to as asthma nervosa in early medical texts.1Osler W. The principles and practice of medicine. YJ Pentland, Edinburgh1892Google ScholarAtopy may be defined as a genetically and environmentally determined predisposition to clinically expressed disorders, including allergic rhinitis, atopic dermatitis or eczema, and allergic asthma, regulated through immune phenomena in which many cells (ie, mast cells, eosinophils, and T lymphocytes) and associated cytokines, chemokines, and neuropeptides play a role. Overlapping mechanisms of inflammation central to the pathophysiology of these atopic disorders involve a cascade of events that include the release of immunologic mediators triggered by both IgE-dependent and IgE-independent mechanisms. Biological hypersensitivity to environmental stimuli is a central feature of atopic disorders. Increasingly, atopy has been conceptualized as an epidemic of dysregulated immunity. The exploration of host and environmental factors that may alter neuroimmune expression and potentiate the expression of atopic disorders is an active area of research. Both genetic and environmental factors affecting maturation of the immune system during childhood set the stage for the inflammatory processes and altered reactivity to stimuli that are characteristic of atopic disorders. Psychological stress may thus play an important role in both the onset of these disorders and the exacerbation of existing atopic disease.It is helpful to begin the discussion by summarizing key aspects of how psychological stress has been conceptualized in human research.2Cohen S, Kessler R, Underwood GL, editors. Strategies for measuring stress in studies of psychiatric and physical disorders. In: Measuring stress: a guide for health and social scientists. New York: Oxford University Press; 1995. p. 3-26.Google Scholar Three broad traditions of assessing the role of psychological stress in disease risk have been distinguished (ie, environmental, psychological, and biological). The environmental tradition focuses on assessment of events associated with adaptive demands, whereas the psychological tradition focuses on the subjective evaluation of one's ability to cope with these demands. If environmental demands are found to be taxing or threatening, and coping resources are viewed to be inadequate, individuals perceive themselves as being under stress.3Lazarus R.S. Folkman S. Stress, appraisal, and coping. Springer, New York1984Google Scholar This perception is presumed to result in negative emotional states (eg, fear, anxiety, posttraumatic stress symptoms, depression). Finally, the biological tradition focuses on activation of specific physiological systems. Behavioral and emotional changes that follow the effort to adapt to stressors are accompanied by complex patterns of neuroendocrine and immunologic alterations.4Chrousos G.P. Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture.Ann N Y Acad Sci. 1998; 851: 311-335Crossref PubMed Scopus (573) Google ScholarTypical stressors considered in health research include factors such as major life events, trauma, and abuse, as well as less intense chronic psychological pressure induced during work and personal relationships.2Cohen S, Kessler R, Underwood GL, editors. Strategies for measuring stress in studies of psychiatric and physical disorders. In: Measuring stress: a guide for health and social scientists. New York: Oxford University Press; 1995. p. 3-26.Google Scholar Exposure to acute stress generates an adaptive individual response, such as “fight or flight.” Chronic stress is generally thought of as the chronic load of day-to-day stressors. Researchers have long recognized that stress may protect the body, but when more chronic, can also damage it.5McEwen B.S. Protective and damaging effects of stress mediators.N Engl J Med. 1998; 338: 171-179Crossref PubMed Scopus (4537) Google Scholar Furthermore, there appear to be individual or host differences in the body's response to similar levels and duration of stress.6Cohen S. Hamrick N. Stable individual differences in physiological response to stressors: implications for stress-elicited changes in immune related health.Brain Behav Immun. 2003; 17: 407-414Crossref PubMed Scopus (100) Google Scholar, 7Cohen S. Frank E. Doyle W.J. Skoner D.P. Rabin B.S. Gwaltney Jr., J.M. Types of stressors that increase susceptibility to the common cold in healthy adults.Health Psychol. 1998; 17: 214-223Crossref PubMed Scopus (389) Google Scholar An individual's response to acute challenges is altered when superimposed on chronic stress.8Pike J.L. Smith T.L. Hauger R.L. Nicassio P.M. Patterson T.L. McClintick J. et al.Chronic life stress alters sympathetic, neuroendocrine, and immune responsivity to an acute psychological stressor in humans.Psychosom Med. 1997; 59: 447-457PubMed Google Scholar, 9Rich E.L. Romero L.M. Exposure to chronic stress downregulates corticosterone responses to acute stressors.Am J Physiol Regul Integr Compar Physiol. 2005; 288: R1628-R1636Crossref PubMed Scopus (314) Google Scholar The reasons behind such individual differences in susceptibility may be key in understanding the functional consequences of chronic psychological stress. These central themes in stress research need to be considered when interpreting studies linking psychological stress and emotion to health outcomes.Mechanisms linking psychological stress, personality, and emotion to neuroimmunoregulation10Cohen S. Herbert T.B. Psychological factors and physical disease from the perspective of human psychoneuroimmunology.Ann Rev Psychol. 1996; 47: 113-142Crossref PubMed Scopus (532) Google Scholar, 11Dantzer R. Innate immunity at the forefront of psychoneuroimmunology.Brain Behav Immun. 2004; 18: 1-6Crossref PubMed Scopus (94) Google Scholar, 12Kelley K.W. From hormones to immunity: the physiology of immunology.Brain Behav Immun. 2004; 18: 95-113Crossref PubMed Scopus (43) Google Scholar as well as increased risk of atopy13Wright R.J. Cohen R.T. Cohen S. The impact of stress on the development and expression of atopy.Curr Opin Allergy Clin Immunol. 2004; 5: 23-29Crossref Scopus (279) Google Scholar have been increasingly elucidated. Advances in our understanding of psychoneuroimmunology and the bidirectional links among the central nervous system (CNS), autonomic nervous system in the periphery, endocrine system, and immune system have been critical. Hormones and neuropeptides released into the circulation when individuals experience stress may also regulate both immune-mediated and neurogenic inflammation. Our current understanding of the role of psychological stress in atopy is discussed. Note that this review focuses specifically on proposed physiological mechanisms linking stress to asthma as summarized in Fig 1. The expression of asthma may also be influenced by behavioral stress responses that have been reviewed previously.14Wright R. Rodriguez M. Cohen S. Review of psychosocial stress and asthma: an integrated biopsychosocial approach.Thorax. 1998; 53: 1066-1074Crossref PubMed Scopus (388) Google ScholarPsychological stress and the endocrine systemPsychological stress has been associated with the activation of the sympathetic and adrenomedullary (SAM) system and the hypothalamic-pituitary-adrenocortical (HPA) axis (see detailed review14Wright R. Rodriguez M. Cohen S. Review of psychosocial stress and asthma: an integrated biopsychosocial approach.Thorax. 1998; 53: 1066-1074Crossref PubMed Scopus (388) Google Scholar). It is the disturbed balance of these systems that is relevant to disease. Immune, metabolic, and neural defensive biological mechanisms important for the short-term response to acute stress may produce long-term damage if not checked and eventually terminated in the face of more chronic stress.5McEwen B.S. Protective and damaging effects of stress mediators.N Engl J Med. 1998; 338: 171-179Crossref PubMed Scopus (4537) Google Scholar Negative emotional responses to environmental stressors disturb the regulation of the HPA axis and the SAM systems; that is, in the face of stress, physiological systems may operate at higher or lower levels than during normal homeostasis. The central notion is that some optimal level of these mediators is necessary to maintain a functional balance, and the absence of this optimal balance in levels of glucocorticoids and catecholamines (for example) allows other immune mediators to overreact and increases the risk of autoimmune and inflammatory disorders. The direction of the HPA response to chronic stress may depend on the nature of the stressor (ie, with respect to duration, severity, controllability, and predictability). Moreover, a well-known characteristic of stress axis functioning is the marked interindividual variability of responses to challenge,6Cohen S. Hamrick N. Stable individual differences in physiological response to stressors: implications for stress-elicited changes in immune related health.Brain Behav Immun. 2003; 17: 407-414Crossref PubMed Scopus (100) Google Scholar and the understanding of the relevance of this neuroendocrine system in asthma and allergy pathophysiology requires the identification of the determinants of this variability. Genetic factors, in utero and postnatal environmental factors, and the timing of exposures likely affect differentiation of this response.Although hormones of the sympathetic and adrenal medullary and HPA systems (eg, cortisol, epinephrine) are those most often discussed as the biological substances involved in stress responses, alterations in a range of other hormones, neurotransmitters, and neuropeptides demonstrated in response to stress may also play a part. Regulatory pituitary (ie, corticotrophin) and hypothalamic hormones (ie, corticotrophin-releasing hormone [CRH] and arginine vasopressin) of the HPA axis have systemic immunopotentiating and proinflammatory effects. Mast cell mediators are responsible for many of the immediate symptoms of nasal allergy and manifestations of atopic dermatitis. Acute psychological stress (immobilization in rats) has been shown to result in skin mast cell degranulation, an effect inhibited by anti-CRH serum administered before stress. Mechanisms linking stress and mast cell function have been extensively reviewed recently.15Theoharides T.C. Donelan J.M. Papadopoulou N. Cao J. Duraisamy K. Conti P. Mast cells as targets of corticotropin-releasing factor and related peptides.Trends Pharmacol Sci. 2004; 25: 563-568Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar For example, stressor-associated increases in substance P, growth hormone, and prolactin secreted by the pituitary gland and in the natural opiate β-endorphins and enkephalins released in the brain are also thought to play a role in immune regulation. Although these factors have been less well studied to date, increasing attention has been given to the role of substance P in mediating inflammatory responses in the lung.Stress and autonomic control of airwaysThe balance between functional parasympathetic and functional sympathetic activity in relation to stress, emotional stimuli, and immune function may also be important for the expression of asthma and allergic rhinitis. Local interactions between the immune system and the autonomic nervous system are only partially understood.16Undem B.J. Kajekar R. Hunter D.D. Myers A.C. Neural integration and allergic disease.J Allergy Clin Immunol. 2000; 106: S213-S220Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 17Bienenstock J, Goetzl EJ, Blennerhassett MG, editors. Autononic neuroimmunology. New York: Taylor & Francis; 2003.Google Scholar Increased activity of the parasympathetic nervous system was once thought to be the dominant mechanism responsible for the exaggerated reflex bronchoconstriction (airway narrowing) that occurs in subjects with asthma, although more recent work challenges this idea. Evidence suggesting several cholinergic anti-inflammatory pathways triggered through vagus nerve activation18Tracey K.J. The inflammatory reflex.Nature. 2002; 420: 853-859Crossref PubMed Scopus (2519) Google Scholar complicate our understanding and need to be explored in the context of atopy.Evidence demonstrating nerve–mast cell communication in response to stress and the potential import of these interactions in the respiratory system suggests this may be a fruitful area of research relative to stress and allergic asthma.17Bienenstock J, Goetzl EJ, Blennerhassett MG, editors. Autononic neuroimmunology. New York: Taylor & Francis; 2003.Google Scholar Tachykinins derived from nonadrenergic noncholinergic (NANC) nerves influence airway smooth muscle contraction, mucus secretion, vascular leakage, and neutrophil attachment. In experimental studies, tachykinins, especially substance P, have been linked to neurogenic inflammation and regulation of stress hormonal pathways and have been implicated in asthma and neurogenic skin disorders.17Bienenstock J, Goetzl EJ, Blennerhassett MG, editors. Autononic neuroimmunology. New York: Taylor & Francis; 2003.Google ScholarWhen immune cells (ie, T cells, mast cells, dendritic cells, and macrophages) are activated locally (eg, in the airways) and release proinflammatory molecular mediators, these signals not only influence cells of the innate and adaptive immunological system in the periphery but also activate sensory pathways that relay information to the CNS.16Undem B.J. Kajekar R. Hunter D.D. Myers A.C. Neural integration and allergic disease.J Allergy Clin Immunol. 2000; 106: S213-S220Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar The precise mechanisms by which the peripheral immune system signals the CNS is only partially understood. Stimulation of sensory nerves in the airways—specifically ascending vagus nerve fibers as well as pain sensory pathways (vagal nonmyelinated lung C fibers and Aδ rapidly adapting receptors)—results in CNS reflex responses consistent with asthma symptoms (eg, bronchoconstriction, cough, mucous secretion). These neural inflammation-sensing pathways can function at low thresholds of detection and activate responses even when inflammatory mediators are present in the airway tissues in quantities too low to reach the brain through the bloodstream. Both animal studies and human imaging data have identified neurobiological correlates that shed further light on neuroimmunological mechanisms underlying the lung-brain link. Airways function in response to stimuli, including irritants, allergens, and inflammatory mediators. Chen et al19Chen C.Y. Bonham A.C. Schlelegle E.S. Gershwin L.J. Plopper C.G. Joad J.P. Extended allergen exposure in asthmatic monkeys induces neuroplasticity in nucleus tractus solitarius.J Allergy Clin Immunol. 2001; 108: 557-562Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 20Chen C.-Y. Bonham A.C. Plopper C.G. Joad J.P. Plasticity in respiratory motor control, selected contribution: neuroplasticity in nucleus tractus solitarius neurons after episodic ozone exposure in infant primates.J Appl Physiol. 2003; 94: 819-827PubMed Google Scholar have demonstrated the ability of the nucleus tractus solitarius, a CNS region containing neurons that process lung sensory signals, to undergo marked changes in excitability in the face of extended exposure to irritants (ie, allergen exposure, ozone exposure, and tobacco smoke). These toxicants share commonalities in the responses they may illicit in the airways (eg, local release of inflammatory mediators, oxidative stress, and activation of sensory neurons) that may contribute to the respiratory inflammatory and motor response. These processes may be mediated, in part, through substance P.21Bonham A.C. Sekizawa S.I. Joad J.P. Plasticity of central mechanisms for cough.Pulm Pharmacol Ther. 2004; 17: 469-470Crossref Scopus (42) Google Scholar A logical extension of this work in the context of this discussion is whether extended episodic exposures to psychological stressors would change the neural behavior of neurons in the CNS and also influence the CNS neural contribution to asthma and the allergic airway response. Further research into the neurobiological correlates of atopy may lead to a more complete understanding of the lung-brain link.Stress and immune functionAtopic inflammation is thought to be orchestrated by activated T lymphocytes and the cytokines they produce. The Th2 cytokine phenotype promotes IgE production, with subsequent recruitment of inflammatory cells that may initiate and/or potentiate allergic inflammation. For most children who develop allergies or asthma, the polarization of their immune system into an atopic phenotype probably occurs during early childhood. These findings have sparked vigorous investigation into the potential influence of early life environmental risk factors for asthma and allergy on the maturation of the immune system, in the hopes of understanding which factors will potentiate (or protect from) this polarization. There is evidence that parental reports of life stress are associated with subsequent onset of wheezing in children in early childhood22Wright R.J. Cohen S. Carey V. Weiss S.T. Gold D.R. Parental stress as a predictor of wheezing in infancy: a prospective birth-cohort study.Am J Respir Crit Care Med. 2002; 165: 358-365Crossref PubMed Scopus (229) Google Scholar (also see references within article22Wright R.J. Cohen S. Carey V. Weiss S.T. Gold D.R. Parental stress as a predictor of wheezing in infancy: a prospective birth-cohort study.Am J Respir Crit Care Med. 2002; 165: 358-365Crossref PubMed Scopus (229) Google Scholar). This relationship led to speculation that stress may trigger hormones in the early months of life, which may in turn influence Th2 cell predominance, perhaps through a direct influence of stress hormones on the production of cytokines that are thought to modulate the direction of differentiation. Further examination of the relationships between caregiver stress on markers of early childhood immune response including IgE expression, mitogen-specific, and allergen-specific lymphocyte proliferative response, and subsequent cytokine expression (IFN-γ, TNF-α, IL-10, and IL-13) was performed in the same prospective birth cohort mentioned23Wright R.J. Finn P.W. Contreras J.P. Cohen S. Wright R.O. Staudenmayer J. et al.Chronic caregiver stress and IgE expression, allergen-induced proliferation, and cytokine profiles in a birth-cohort predisposed to atopy.J Allergy Clin Immunol. 2004; 113: 1051-1057Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar when the children were 2 to 3 years of age. In adjusted analyses, higher caregiver stress in the first 6 months after birth was associated with increases in the children's allergen-specific proliferative response (a marker of the allergic immune response), higher total IgE levels, and increased production of TNF-α and reduced IFN-γ.Recent animal data suggest that increased maternal stress prenatally is associated with an elevated cortisol response to stress in the newborn, affecting Th1/Th2 cell differentiation.24von Hertzen L.C. Maternal stress and T-cell differentiation of the developing immune system: possible implications for the development of asthma and atopy.J Allergy Clin Immunol. 2002; 109: 923-928Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar Although the ability to activate an increase in cortisol in response to some stimuli in early life may be adaptive, prolonged exposure to stress may change the cortisol response if examined at a later developmental stage. Chronic stress may induce a state of hyporesponsiveness of the HPA axis whereby cortisol secretion is attenuated, leading to a shift in the balance of proinflammatory/anti-inflammatory cytokines secreted (ie, increased production of proinflammatory cytokines typically counterregulated by cortisol). Several altered neuroendocrine and immune changes in response to stress have been demonstrated in subjects with atopic dermatitis: altered responsiveness of the HPA axis and the SAM system, increased eosinophil counts, and elevated IgE expression.25Buske-Kirschbaum A. Fischbach S. Rauh W. Hanker J. Hellhammer D. Increased responsiveness of the hypothalamus-pituitary-adrenal (HPA) axis to stress in newborns with atopic disposition.Psychoneuroendocrinology. 2004; 29: 705-711Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Whether the altered HPA responsiveness will lead to increased risk of developing atopy in later life remains to be seen. A state of stress-induced HPA hyporesponsiveness has been demonstrated in some research subjects with chronic atopic disorders.26Wamboldt M.Z. Laudenslager M. Wamboldt F.S. Kelsay K. Hewitt J. Adolescents with atopic disorders have an attenuated cortisol response to laboratory stress.J Allergy Clin Immunol. 2003; 111: 509-514Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar An attenuated cortisol response has been found among adolescents with positive skin test reactivity and a clinical history of allergic rhinitis, atopic dermatitis, or asthma compared with those with skin test positivity alone or nonatopic individuals. Further studies are needed to examine relationships between individual patterns of cortisol response to stress across different developmental periods and the subsequent expression of atopy.Stress and glucocorticoid resistanceAn alternative hypothesis linking stress, neuroendocrine and immune function, and inflammatory disease expression considers a glucocorticoid resistance model.27Miller G.E. Cohen S. Ritchey A.K. Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model.Health Psychol. 2002; 21: 531-541Crossref PubMed Scopus (689) Google Scholar As we have come to understand the central role of airway inflammation and immune activation in asthma pathogenesis, asthma treatment guidelines have focused on the use of anti-inflammatory therapy, particularly oral and inhaled glucocorticoids or steroids. Patients with asthma, however, have a variable response to glucocorticoid therapy. Although the majority of patients readily respond, a subset of patients has difficult-to-control asthma even when treated with high doses. Notably, the majority of subjects with glucocorticoid-resistant or glucocorticoid-insensitive asthma have an acquired form of steroid resistance thought to be induced by chronic inflammation or immune activation. Thus, it is important to investigate those factors that may potentiate the development of functional steroid resistance so that we might intervene to prevent or reverse it. It has been proposed that chronic psychological stress, resulting in prolonged activation of the HPA and SAM axes, may result in a counterregulatory response in stimulated lymphocytes and consequent downregulation of the expression and/or function of glucocorticoid receptors leading to functional steroid resistance.27Miller G.E. Cohen S. Ritchey A.K. Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model.Health Psychol. 2002; 21: 531-541Crossref PubMed Scopus (689) Google Scholar, 28Chrousos G.P. Castro M. Leung D.Y. Webster E. Kino T. Bamberger C. et al.Molecular mechanisms of glucocorticoid resistance/hypersensitivity: potential clinical implications.Am J Respir Crit Care Med. 1996; 154 (discussion S44): S39-S43Crossref PubMed Google Scholar This in part may be mediated through downregulation of the gene coding for the expression of the glucocorticoid receptor (Miller G, personal communication, September 2005).Relevance of perinatal physiological programming and early life stressStudies suggest that characteristics of the in utero environment, independent of genetic susceptibility, influence fetal development, including immune development.29Gluckman P.D. Cutfield W. Hofman P. Hanson N.A. The fetal, neonatal, and infant environments—the long-term consequences for disease risk.Early Hum Dev. 2005; 81: 51-59Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, 30Shanks N. Lightman S.L. The maternal-neonatal neuro-immune interface: are there long-term implications for inflammatory or stress-related disease?.J Clin Invest. 2001; 108: 1667-1673PubMed Google Scholar The concept that nongenetic factors act early in life to organize or imprint physiological systems permanently is known as perinatal programming. Adverse environmental influences at critical periods of development (ie, stress) may be important in this regard. The HPA axis seems particularly susceptible to early life programming.31Welberg L. Seckl J. Prenatal stress, glucocorticoids and the programming of the brain.J Neuroendocr. 2001; 17: 113-128Crossref Google Scholar Maternal and fetal stress stimulates placental secretion of CRH, which in turn may stimulate the fetal HPA axis to secrete glucocorticoids, amplifying fetal glucocorticoid excess. These in utero responses may be adaptive in the short term (ie, increasing the availability of glucose and other fuels), geared toward coping with predicted increased environmental challenges, but they exact a toll in that there is an increased risk of disease in later life. Moreover, gestational exposure to maternal stress has been shown to alter the development of humoral immunocompetence in offspring as well as their hormonal and immunologic responses to postnatal stress.32Barker D.J. A new model for the origins of chronic disease.Med Health Care Philos. 2001; 4: 31-35Crossref PubMed Scopus (87) Google ScholarEarly childhood environment can also affect these processes. Studies in both rodents and primates have shown that environmental manipulations that increase maternal stress result in elevated cortisol levels and dysfunctional behaviors in offspring that are evident later in life, which may be mediated, in part, through effects on gene expression.33Meaney M.J. Szyf M. Maternal care as a model for experience-dependent chromatin plasticity?.Trends Neurosci. 2005; 28: 456-463Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar Numerous retrospective studies in human HPA functioning suggest that increased reactivity of the HPA system is associated with early life trauma and severe deprivation. Studies of infants and toddlers have linked maternal depression to dysregulation of the child's HPA axis in both cross-sectional and longitudinal studies. Other studies of preschoolers and older children suggest that children's cortisol levels are positively correlated with numerous social stresses and to broader family characteristics known to be associated with higher stress levels (eg, low socioeconomic status). For example, Essex et al34Essex M.J. Klein M.H. Cho E. Kalin N.H. Maternal stress beginning in infancy may sensitize children to later stress exposure: effects on cortisol and behavior.Biol Psychiatry. 2002; 52: 776-784Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar examined the relationships of maternal stress beginning in infancy and concurrent stress on preschoolers' (age 4.5 years) HPA activity and later mental health outcomes. A cross-sectional analysis revealed that preschoolers exposed to high levels of concurrent maternal stress had elevated cortisol levels. Longitudinal analyses showed that concurrently stressed children with elevated cortisol also had a history of high maternal stress exposure in infancy. Importantly, children exposed only to high levels of concurrent or early stress had cortisol levels that did not significantly differ from those never exposed to stress. Also of note, further analysis of the components of stress indicated that maternal depression beginning in infancy was the most potent predictor of children's cortisol. Preschoolers with high cortisol levels also were more likely to have greater mental health difficulties in first grade. Future studies should be designed to examine whether the link between early stress (specifically maternal stress even starting in pregnancy) and later expression of asthma/wheeze clinical and immune phenotypes is in part mediated through dysregulation of the HPA axis.Psychological stress and oxidative stressOxidative stress pathways also play an important role in the regulation of inflammatory mediators t
Referência(s)