Sudden infant death syndrome Part 2: the response of the reticuloendothelial system to hypoxemia and infection

Abstract 

The incidence of ascites in chicks raised in a high-altitude chamber doubled from 6500 feet to 8000 feet. A similar condition developed in calves transported to pasture at high altitude. Chicks raised in a high-altitude chamber (compared to controls) produced more plasma cells in the germinal centres of the spleen about four days after an antigen challenge. Children usually suffering from a mild respiratory infection at sea level often developed pulmonary edema (HAPE) on transfer to high altitude. Sudden infant death syndrome (SIDS) victims produced more plasma cells in the germinal centers of the spleen. In one survey of SIDS, about half of the infants suffered an upper respiratory tract infection in the two weeks prior to death and the lungs were filled with fluid at autopsy. Elevated levels of hypoxanthine indicated hypoxemia before death, and a presumed response to hypoxemia in SIDS was the presence of extramedullary hematopoiesis in the liver.

The effect of prolonged hypoxemia and infection are additive in increasing vascular permeability and the accumulation of edema fluid. The preferential uptake of zinc by edema fluid proteins at the expense of inflammatory cells increases the motility and metabolism of zinc-deprived activated macrophages. Activated macrophages release cytokines which in turn stimulate the release of pro-inflammatory peptides which increase vascular permeability and mortality. These inflammatory peptides are under proteolytic control. The neutral endopeptidase (NEP) is a cell-surface zinc metalloproteinase which modulates toxic shock.

Zinc also modulates the inflammatory response of the activated macrophage. Interleukin-12 (IL-12), predominantly a product of macrophages, is involved in regulating both hematopoiesis and the adaptive immune response. IL-12 promotes interferon γ (IFNγ) production by T cells. IFNγ acts on macrophages to release large amounts of nitric oxide (NO). An elevated immune response leads to NO overload, dilation of the cardiovascular system and toxic shock. A mechanism resulting in cardiovascular failure and a shock-like sequence is described in some cases of SIDS.

Bradycardia, recorded on cardiorespiratory monitors in six SIDS infants, was considered a late event. Cytokines regulate all aspects of the immune response.

Extramedullary hematopoiesis in the liver was one anatomical marker of hypoxemia in SIDS. This survey traces the function of the activated macrophage with the cytokines regulating extramedullary hematopoiesis and the precocious immune response in SIDS.

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