SnapShot: Stress and Disease
Stress is defined as any threat to an organism that triggers adaptations at a molecular, cellular, physiological, or behavioral level. Chronic activation, orchestrated by the SNS and HPA via stress hormones (NE, Epi, and cortisol), plays a key role in physiology and disease. In general, postganglionic neurons release NE, but there are two excep-tions: postganglionic neurons of sweat glands (releasing acetylcholine) and chromaffin cells of the adrenal medulla (releasing Epi and NE).
Immune System
Stress exerts pleiotropic effects on the immune system and compromises both innate and adaptive immune responses. Stress hormones can act directly on macrophages, dendritic cells, T cells, B cells, and NK cells via GR and/or adrenergic receptors. NE increases proinflammatory molecules (CRP and IL6), whereas persistently high GCs reduce inflammation and induce immune suppression via NF-κB-, AP1-, Raf-, and MAPK-mediated signaling. Epidemiological studies indicate that chronic stress increases neutrophil and inflammatory monocyte numbers and stimulates mast cell degranulation. Chronic stress also attenuates peripheral blood T cell proliferation, reduces T cell control of latent viruses (Epstein-Barr and herpesviruses), and increases the risk of bacterial infection (e.g., H. pylori
Cardiovascular Disease
Epidemiological studies link chronic stress with increased risk of myocardial ischemia or infarction and cardiac wall motion abnormalities. Of note, 16%-23% of all patients with CVD suffer from clinical depression. High plasma NE levels are associated with increased risk of heart failure. Altered autonomic activity during depression can lead to arrhythmias. Takotsubo cardiomyopathy, another stress-related myocardial disorder, is characterized by the sudden weakening of the myocardium in response to acute stress. SNS hypersensitivity alters cardiac wall contractility and increases apoptotic pathways in cardiomyocytes, contributing to CVD development. Stress also increases plaque rupture, leading to atherosclerosis, likely via adrenergic signaling in platelets
Brain
NE directly stimulates dopaminergic neurons in the midbrain and the brain stem, resulting in anxiety-like behavior and depression. Stress-induced activation of the SNS increases the firing of brain neurons in prefrontal cortex and amygdala and contributes to development of hypertension and depression. Stress compromises neuronal plastic-ity in the hippocampus, leading to psychiatric disorders (depression). In preclinical models, chronic restraint stress disrupts serotonin (5-HT) secretion in the prefrontal cortex, leading to abnormal morphology and atrophy of pyramidal cells. Patients with depression have altered HPA activity, blunted circadian rhythm, and elevated cortisol, primarily due to GR dysfunction such as reduced GR expression, lower binding affinity, impaired nuclear translocation, or interaction with other transcription factors (NF-κB, AP1). Such dysfunction paradoxically elevates levels of proinflammatory cytokines. Further, increased cortisol promotes atrophy of nerves within the hippocampus, leading to loss of hippocampal volume
.Cancer
Epidemiological studies implicate severe life stressors in breast cancer initiation, whereas studies on rodents solidify the role of chronic stress as a driver of ovarian, breast, and prostate cancer growth and metastasis.
Chronic stress may lead to epigenetic heritable modifications, suggesting a possible propagation across generations. In an ovar-ian carcinoma mouse model, daily restraint stress increased tumor burden and enhanced angiogenesis and tumor production of vascular endothelial growth factor (VEGF). NE also promotes resistance to anoikis, inhibits apoptosis, and increases tumor cell invasion and metastasis, macrophage infiltration, and chemoresistance
.Colon
Stress can trigger the onset of IBS, a chronic lower gastrointestinal tract disorder characterized by abdominal pain and distension, visceral hypersensitivity, disturbed gastrointestinal motility, and changes in stool form or frequency. IBS is associated with increased intestinal permeability related to release of acetylcholine and CRH and to activation of muscarinic receptor. Patients with IBS show altered function of HPA axis with blunted ACTH levels and elevated cortisol.Chronic stress can predispose to IBD that arises from inappropriate activation of the mucosal immune system, leading to chronic inflammation and epithelial injury. IBD patients have elevated levels of IL1β, IL6, IL8, IFNγ, and TNFα. Genome-wide association studies have identified IBD susceptibility loci containing genes associated with cyto-kine and chemokine signaling (e.g., chemokine ligands, several ILs, IFNγ, and STAT proteins) that can be influenced by adrenergic signaling.IBD patients have increased risk of colitis-associated colorectal cancer. Biobehavioral stress factors directly stimulate growth and progression of colon cancer cells. Rodent studies show that NE and Epi promote colon cancer growth, which is attenuated by α- and/or β-adrenergic receptor antagonists. Epidemiological studies also sug-gest that β-blockers may reduce colon cancer progression, but randomized prospective studies are needed. Recently, NE was found to enhance pathogenic bacterial growth and attachment to colon cancer cells, revealing the involvement of the gut microbiome in colorectal cancer development.
Metabolic Disease
Chronic stress plays an important role in several metabolic diseases. In preclinical models of obesity, cortisol is implicated in reduced insulin secretion. NE turnover in brown adipose tissue is decreased, resulting in decreased thermogenesis; increased HPA axis activity plays a prominent role in diabetes, and GC are associated with both decreased insulin sensitivity in liver and decreased glucose transport in skeletal muscle, adipocytes, and hippocampal astrocytes
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