Mechanisms of ARDS in Children and Adults
Mechanisms of ARDS in Children and Adults
Pneumonia and sepsis are the most commonly identified etiologies of ARDS in children and adults, and the innate immune system has been the focus of many ARDS studies.
The innate immune system is highly conserved, and although its function is not dependent on prior exposure to pathogens, it is not fully functional at birth. Infants are more susceptible than adults to a wide variety of infectious agents. Neonatal neutrophil responses are limited by reduced granulocyte colony-stimulating factor production, combined with a limited neutrophil storage pool. There is also evidence that neutrophil demargination and migration to sites of infection are decreased. Lower neonatal polymorphonuclear (PMN) cell chemotactic activity as compared with adults may be due to differences in complement activation, collectins, and fibronectin concentrations. The decreased chemotactic responses of human neonatal PMN may persist for as long as 1–2 years before reaching full adult levels of responsiveness. Plasma levels of soluble intercellular adhesion molecule-1, a molecule involved in neutrophil adhesion and migration, have been associated with worse clinical outcome in children and adults with ARDS.
Neonatal inflammatory responses to bacterial products, such as lipopolysaccharide (LPS), are reduced as compared with adults. In vitro studies of neonatal PMNs, monocytes, and whole cord blood stimulated with LPS have shown that infants have lower tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-12 responses as compared with adults. Adult PMNs up-regulate membrane CD14 (an important coreceptor for toll-like receptor (TLR)4-dependent recognition of LPS) in response to LPS, whereas similarly treated infant PMNs do not significantly change membrane CD14 expression. Lower infant TNF-α responses as compared with adults have also been correlated with lower expression of myeloid differentiation primary response protein 88 (MyD88, a necessary intracellular adaptor protein for most TLR signaling) levels in mononuclear cells.
Little is known about lung macrophages in the human neonate, but the alveolar macrophages of neonates of many species have reduced microbicidal activity. Macrophage chemotaxis in children is thought to be reduced until 6–10 years old, and cytokine production in neonatal macrophages treated with TLR2 and TLR4 agonists is only 25–75% of that seen in adult macrophages. Although the developmental changes in monocyte expression of TLR3 receptors or responses to TLR3 agonists are not known, the responses of neonatal macrophages to viral pathogens are impaired, with interferon (IFN)-α/β production as low as 10–30% of the values of adult macrophages.
NF-κB is a transcription factor present in almost all mammalian cells, and NF-κB regulates cell differentiation and organ morphogenesis as well as inflammatory and apoptotic responses to external and internal stimuli. The canonical pathway involves phosphorylation of IκB proteins, releasing cytosolic NF-κB dimers (predominantly p65p50) to translocate into the nucleus. Under resting conditions, p50 and p65 subunits are abundant, with p65p50 heterodimers bound to IκB in the cytoplasm and unbound nuclear p50p50 homodimers. In studies by Yang et al (53), neonatal but not adult mice were shown to activate NF-κB in the lungs in response to hyperoxia, and p50 null mutant neonatal mice treated with hyperoxia developed increased lung inflammation and apoptosis and lowered survival as compared with age-matched wild-type mice. Age-dependent differences in NF-κB were also found in studies by Alvira et al (54), in which the dimerization of NF-κB subunits was shown to differ in the lungs of neonatal and adult mice treated with LPS. Interestingly, the formation of p50p50 homodimers in the lungs of adult mice was associated with increased inflammation and apoptosis in the lungs as compared with neonatal mice, in which p65p50 heterodimers predominated. Age-dependent mechanisms regulating NF-κB dimerization and the age-dependent transcriptional responses to the NF-κB dimers are poorly understood.
IL-1β has been associated with lung injury in rodents and humans. Polymorphisms in the IL-1 receptor antagonist gene have been associated with the systemic inflammatory responses in adults and the development of ARDS in children with community-acquired pneumonia. In an experimental model of ARDS, the combination of LPS and mechanical ventilation caused synergistic increases in the amount of IL-1β in adult but not juvenile mice.
There are many important intersections between the regulation of innate immunity and lung growth, development, and repair. A balanced pro- and anti-inflammatory response resulting in rapid clearance of pathogens is necessary to survive a severe infection. Infants appear to be at one end of the spectrum of innate immune function, such that they lack injurious proinflammatory responses, but pathogen clearance is impaired. Adults appear to be at the other end of the spectrum of innate immune function, as they are able to clear pathogens rapidly, but often succumb to their own proinflammatory responses. Translational studies are needed to understand how the apparent balance in inflammatory responses differs across the spectrum of age. The results of these studies have potential to lead to novel therapeutic approaches to balancing the inflammatory responses in patients of all ages.
Innate Immunity in the Lungs
Pneumonia and sepsis are the most commonly identified etiologies of ARDS in children and adults, and the innate immune system has been the focus of many ARDS studies.
The innate immune system is highly conserved, and although its function is not dependent on prior exposure to pathogens, it is not fully functional at birth. Infants are more susceptible than adults to a wide variety of infectious agents. Neonatal neutrophil responses are limited by reduced granulocyte colony-stimulating factor production, combined with a limited neutrophil storage pool. There is also evidence that neutrophil demargination and migration to sites of infection are decreased. Lower neonatal polymorphonuclear (PMN) cell chemotactic activity as compared with adults may be due to differences in complement activation, collectins, and fibronectin concentrations. The decreased chemotactic responses of human neonatal PMN may persist for as long as 1–2 years before reaching full adult levels of responsiveness. Plasma levels of soluble intercellular adhesion molecule-1, a molecule involved in neutrophil adhesion and migration, have been associated with worse clinical outcome in children and adults with ARDS.
Neonatal inflammatory responses to bacterial products, such as lipopolysaccharide (LPS), are reduced as compared with adults. In vitro studies of neonatal PMNs, monocytes, and whole cord blood stimulated with LPS have shown that infants have lower tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-12 responses as compared with adults. Adult PMNs up-regulate membrane CD14 (an important coreceptor for toll-like receptor (TLR)4-dependent recognition of LPS) in response to LPS, whereas similarly treated infant PMNs do not significantly change membrane CD14 expression. Lower infant TNF-α responses as compared with adults have also been correlated with lower expression of myeloid differentiation primary response protein 88 (MyD88, a necessary intracellular adaptor protein for most TLR signaling) levels in mononuclear cells.
Little is known about lung macrophages in the human neonate, but the alveolar macrophages of neonates of many species have reduced microbicidal activity. Macrophage chemotaxis in children is thought to be reduced until 6–10 years old, and cytokine production in neonatal macrophages treated with TLR2 and TLR4 agonists is only 25–75% of that seen in adult macrophages. Although the developmental changes in monocyte expression of TLR3 receptors or responses to TLR3 agonists are not known, the responses of neonatal macrophages to viral pathogens are impaired, with interferon (IFN)-α/β production as low as 10–30% of the values of adult macrophages.
NF-κB is a transcription factor present in almost all mammalian cells, and NF-κB regulates cell differentiation and organ morphogenesis as well as inflammatory and apoptotic responses to external and internal stimuli. The canonical pathway involves phosphorylation of IκB proteins, releasing cytosolic NF-κB dimers (predominantly p65p50) to translocate into the nucleus. Under resting conditions, p50 and p65 subunits are abundant, with p65p50 heterodimers bound to IκB in the cytoplasm and unbound nuclear p50p50 homodimers. In studies by Yang et al (53), neonatal but not adult mice were shown to activate NF-κB in the lungs in response to hyperoxia, and p50 null mutant neonatal mice treated with hyperoxia developed increased lung inflammation and apoptosis and lowered survival as compared with age-matched wild-type mice. Age-dependent differences in NF-κB were also found in studies by Alvira et al (54), in which the dimerization of NF-κB subunits was shown to differ in the lungs of neonatal and adult mice treated with LPS. Interestingly, the formation of p50p50 homodimers in the lungs of adult mice was associated with increased inflammation and apoptosis in the lungs as compared with neonatal mice, in which p65p50 heterodimers predominated. Age-dependent mechanisms regulating NF-κB dimerization and the age-dependent transcriptional responses to the NF-κB dimers are poorly understood.
IL-1β has been associated with lung injury in rodents and humans. Polymorphisms in the IL-1 receptor antagonist gene have been associated with the systemic inflammatory responses in adults and the development of ARDS in children with community-acquired pneumonia. In an experimental model of ARDS, the combination of LPS and mechanical ventilation caused synergistic increases in the amount of IL-1β in adult but not juvenile mice.
There are many important intersections between the regulation of innate immunity and lung growth, development, and repair. A balanced pro- and anti-inflammatory response resulting in rapid clearance of pathogens is necessary to survive a severe infection. Infants appear to be at one end of the spectrum of innate immune function, such that they lack injurious proinflammatory responses, but pathogen clearance is impaired. Adults appear to be at the other end of the spectrum of innate immune function, as they are able to clear pathogens rapidly, but often succumb to their own proinflammatory responses. Translational studies are needed to understand how the apparent balance in inflammatory responses differs across the spectrum of age. The results of these studies have potential to lead to novel therapeutic approaches to balancing the inflammatory responses in patients of all ages.
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