Mechanisms of ARDS in Children and Adults
Mechanisms of ARDS in Children and Adults
Injury to the alveolar epithelium and/or endothelium results in the accumulation of protein-rich edema fluid in the alveolar air spaces, which inactivates surfactant and increases the diffusion distance for gas exchange. Clearance of fluid from the alveolar airspace requires an intact alveolar epithelial barrier, and adult patients with low alveolar fluid clearance rates had a longer duration of mechanical ventilation, worse oxygenation, and higher mortality as compared with adults who had normal to maximal alveolar fluid clearance rates. Although cumulative fluid balance has been shown to correlate with mortality in pediatric and adult ARDS patients, alveolar fluid clearance does not equate with fluid balance.
Epithelial sodium channels, the cystic fibrosis transmembrane conductance regulator, Na+-K+-ATPase, and aquaporins (cell membrane water channels) are involved in the clearance of fluid from the distal airspaces into the interstitium of the lung. Salt and water transport is regulated by catecholamines, glucocorticoids, mineralocorticoids, growth factors (epidermal growth factor, TGF-α, keratinocyte growth factor [KGF], or FGF-7), FGF-10, NF-κB, and serine proteases.
Male gender has been associated with low alveolar fluid clearance in adult patients with ARDS, whereas premenopausal women were more likely to have high alveolar fluid clearance. These findings are supported by animal data showing that progesterone and estrogen increased expression and function of the epithelial sodium channel. Beta-adrenergic agonists up-regulate alveolar fluid clearance in human lungs. However, two randomized placebo-controlled trials of treatment with IV salbutamol did not show a reduction in ventilator-free days or mortality in adults with ARDS. Animal studies of KGF therapy for acute lung injury have suggested that pre- but not postinjury treatment is protective, but there is an ongoing trial in the United Kingdom investigating the effect of treatment with KGF in adult patients with lung injury (http://www.controlled-trials.com/ISRCTN95690673/).
Children have not been included in studies of alveolar fluid clearance in patients with ARDS, and nothing is known about the rate of alveolar fluid clearance in children with ARDS as compared with adults. However, experimental models of alveolar fluid clearance may provide clues to mechanisms by which alveolar fluid clearance in children with ARDS could be different from adults. KGF/FGF-7 increases clearance of alveolar fluid, and it is an alveolar cell mitogen that is up-regulated in injured lungs. Pretreatment with KGF before lung injury preserves alveolar fluid clearance, is protective in several models of lung injury, and it is not clear why treatment with KGF after injury in animal models has not been beneficial. KGF is an important mediator of postnatal lung morphogenesis. Therefore, throughout childhood, the lung may be "pretreated" with KGF before any insult actually occurs.
Future studies of the rate of alveolar fluid clearance in children and adults with ARDS are necessary in order to determine whether alveolar fluid clearance is better preserved in children with ARDS versus adults. Since preservation of alveolar fluid clearance has been associated with decreased mortality in adults with ARDS, identifying a population with higher alveolar fluid clearance may lead to identification of therapeutic interventions that are beneficial for all patients with impaired alveolar fluid clearance.
Alveolar Fluid Transport
Injury to the alveolar epithelium and/or endothelium results in the accumulation of protein-rich edema fluid in the alveolar air spaces, which inactivates surfactant and increases the diffusion distance for gas exchange. Clearance of fluid from the alveolar airspace requires an intact alveolar epithelial barrier, and adult patients with low alveolar fluid clearance rates had a longer duration of mechanical ventilation, worse oxygenation, and higher mortality as compared with adults who had normal to maximal alveolar fluid clearance rates. Although cumulative fluid balance has been shown to correlate with mortality in pediatric and adult ARDS patients, alveolar fluid clearance does not equate with fluid balance.
Epithelial sodium channels, the cystic fibrosis transmembrane conductance regulator, Na+-K+-ATPase, and aquaporins (cell membrane water channels) are involved in the clearance of fluid from the distal airspaces into the interstitium of the lung. Salt and water transport is regulated by catecholamines, glucocorticoids, mineralocorticoids, growth factors (epidermal growth factor, TGF-α, keratinocyte growth factor [KGF], or FGF-7), FGF-10, NF-κB, and serine proteases.
Male gender has been associated with low alveolar fluid clearance in adult patients with ARDS, whereas premenopausal women were more likely to have high alveolar fluid clearance. These findings are supported by animal data showing that progesterone and estrogen increased expression and function of the epithelial sodium channel. Beta-adrenergic agonists up-regulate alveolar fluid clearance in human lungs. However, two randomized placebo-controlled trials of treatment with IV salbutamol did not show a reduction in ventilator-free days or mortality in adults with ARDS. Animal studies of KGF therapy for acute lung injury have suggested that pre- but not postinjury treatment is protective, but there is an ongoing trial in the United Kingdom investigating the effect of treatment with KGF in adult patients with lung injury (http://www.controlled-trials.com/ISRCTN95690673/).
Children have not been included in studies of alveolar fluid clearance in patients with ARDS, and nothing is known about the rate of alveolar fluid clearance in children with ARDS as compared with adults. However, experimental models of alveolar fluid clearance may provide clues to mechanisms by which alveolar fluid clearance in children with ARDS could be different from adults. KGF/FGF-7 increases clearance of alveolar fluid, and it is an alveolar cell mitogen that is up-regulated in injured lungs. Pretreatment with KGF before lung injury preserves alveolar fluid clearance, is protective in several models of lung injury, and it is not clear why treatment with KGF after injury in animal models has not been beneficial. KGF is an important mediator of postnatal lung morphogenesis. Therefore, throughout childhood, the lung may be "pretreated" with KGF before any insult actually occurs.
Future studies of the rate of alveolar fluid clearance in children and adults with ARDS are necessary in order to determine whether alveolar fluid clearance is better preserved in children with ARDS versus adults. Since preservation of alveolar fluid clearance has been associated with decreased mortality in adults with ARDS, identifying a population with higher alveolar fluid clearance may lead to identification of therapeutic interventions that are beneficial for all patients with impaired alveolar fluid clearance.
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