Possible Pathomechanisms of Sudden Infant Death Syndrome

Abstract

Chronic hypoxia, viral infections/bacterial toxins, inflammation states, biochemical disorders, and genetic abnormalities are the most likely trigger of sudden infant death syndrome (SIDS). Autopsy studies have shown increased pulmonary density of macrophages and markedly more eosinophils in the lungs accompanied by increased T and B lymphocytes. The elevated levels of immunoglobulins, about 20% more muscle in the pulmonary arteries, increased airway smooth muscle cells, and increased fetal hemoglobin and erythropoietin are evidence of chronic hypoxia before death. Other abnormal findings included mucosal immune stimulation of the tracheal wall, duodenal mucosa, and palatine tonsils, and circulating interferon. Low normal or higher blood levels of cortisol often with petechiae on intrathoracic organs, depleted maternal IgG antibodies to endotoxin core (EndoCAb) and early IgM EndoCAb triggered, partial deletions of the C4 gene, and frequent IL-10-592*A polymorphism in SIDS victims as well as possible hypoxia-induced decreased production of antiinflammatory, antiimmune, and antifibrotic cytokine IL-10, may be responsible for the excessive reactions to otherwise harmless infections. In SIDS infants, during chronic hypoxia and times of infection/inflammation, several proinflammatory cytokines are released in large quantities, sometimes also representing a potential source of tissue damage if their production is not sufficiently well controlled, eg, by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). These proinflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting metabolism of several endogenous lipophilic substances, such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances. In SIDS victims, chronic hypoxia, TNF-alpha and other inflammatory cytokines, and arachidonic acid (AA) as well as n-3 polyunsaturated fatty acids (FA), stimulated and/or augmented superoxide generation by polymorphonuclear leukocytes, which contributed to tissue damage. Chronic hypoxia, increased amounts of nonheme iron in the liver and adrenals of these infants, enhanced activity of CYP2C9 regarded as the functional source of reactive oxygen species (ROS) in some endothelial cells, and nicotine accumulation in tissues also intensified production of ROS. These increased quantities of proinflammatory cytokines, ROS, AA, and nitric oxide (NO) also resulted in suppression of many CYP450 and other enzymes, eg, phosphoenolpyruvate carboxykinase (PEPCK), an enzyme important in the metabolism of FA during gluconeogenesis and glyceroneogenesis. PEPCK deficit found in SIDS infants (caused also by vitamin A deficiency) and eventually enhanced by PACAP lipolysis of adipocyte triglycerides resulted in an increased FA level in blood because of their impaired reesterification to triacylglycerol in adipocytes. In ...

The induced prostaglandin E 2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates

“…To further elucidate the mechanism underlying the association between infection and apnea in human newborns, we examined the association between the infectious marker C-reactive protein (CRP), CSF PGE 2 levels, and apnea events in newborn infants. CRP was positively correlated with central PGE 2 , and there was a positive association between PGE 2 concentrations in the CSF and apnea frequency (Fig. 5).…”

“…Apnea is a common presenting sign of infection in neonates, and mild viral or bacterial infection precedes death in the majority of SIDS victims (1,2). Proinflammatory cytokines such as IL-1␤ may serve as key mediators between these events (3).…”

“…PGE 2 itself depresses breathing in fetal and newborn sheep in vivo (17)(18)(19) and inhibits respiration-related neurons in vitro (5). Furthermore, EP3 receptors (EP3R) for PGE 2 are located in the NTS and RVLM (20,21).…”

Secondhand smoke exposure and serum cytokine levels in healthy children

“…A variety of diseases are associated with SHS exposure, including lower respiratory infections, 1 asthma, 2,3 sudden infant death syndrome, 3 inflammatory bowel disease, 4 otitis media, 5 metabolic syndrome , 6 and leukemia. 7 It is estimated that each year in the US, 202,300 new cases of asthma, 300,000 cases of lower respiratory illnesses, and 789,700 ear infections develop due to SHS exposure in children.…”

Limitations in the Clinical Usefulness of Single-Dose Pharmacokinetic Studies of Drugs and a Bayesian Approach for the Estimation of Kinetic Parameters

“…9,38 Another example that highlights clinical importance of depression of metabolism during infection and/or inflammation states is that down-regulation of phosphoenolpyruvate carboxykinase (PEPCK) activity and expression by tumor necrosis factor, IL-1, IL-6, bacterial endotoxin, adenovirus E1A, oxidative stress, and vitamin A deficiency plays a key role in possible pathomechanisms of sudden infant death syndrome (SIDS). 40,41 The repression of PEPCK activity caused impairment of gluconeogenesis and glyceroneogenesis in the liver and/or adipocytes of SIDS infants, which probably resulted in overproduction and eventual accumulation of non-estrified fatty acids, the biochemical disturbances characteristic for the early phase of type 2 diabetes. 42 All of these metabolic disturbances, combined with chronic hypoxia and nicotine exposure reported in SIDS victims, prompted the release of numerous proinflammatory cytokines and the generation of neutrophil oxygen radicals that intensified down-regulation of several CYP450 and other enzyme activity, finally leading to metabolic trauma and the death of these frequently genetically predisposed children.…”