Abstract
Extract: Plasminogen-activator activity was measured in lungs from 7 newborn premature infants examined at autopsy (control lungs) and 11 infants dying of hyaline membrane disease (hyaline membrane lungs) and was reevaluated by using human and rabbit fibrin substrates in addition to the traditional bovine fibrin substrate. The whole homogenate and the supernatant and sediment fractions from the lungs of the normal infants were active when tested on unheated human, bovine, and rabbit fibrin plates. In comparison, 10 of the 11 specimens of hyaline membrane lungs failed to lyse either bovine or human fibrin when the whole homogenate or the supernatant or sediment fractions were tested. Rabbit fibrin substrate was digested by all the hyaline membrane lung homogenates, but only after a prolonged incubation period. Mixtures of the supernatant fraction from any of the 10 hyaline membrane specimens, plus equal volumes of lung homogenate from a normal infant, resulted in total inhibition of normal plasminogen-activator activity.
Mixture of 0.05 ml 2M KSCN with 0.1 ml normal lung homogenate enhanced plasminogen-activator activity by approximately 80% using human, bovine, or rabbit fibrin substrates. The addition of thiocyanate also induced plasminogen-activator activity of homogenates from 11 hyaline-membrane lungs. Three of these 11 specimens caused lysis of heated human fibrin plates in the presence of thiocyanate, indicating direct protease activity.
Extraction of the hyaline-membrane lungs with thiocyanate by the method of ASTRUP and Albreghtsen[5] revealed plasminogen-activator activity in all specimens. None of the thiocyanate extracts caused lysis of heated fibrin plates. Thus, the direct proteolytic activity, induced in some lung homogenates by the addition of thiocyanate, did not survive the acid precipitation phase of the thiocyanate extraction procedure.
Saline extracts (supernatants) of 11 hyaline membrane and 7 control lungs were tested on unheated and heated human fibrin plates with the addition of either 2M KSGN or water to determine whether thiocyanate enhanced activator activity by increasing the solubility of the enzyme or by direct enhancement of enzyme activity. Activator activity of the supernatant fractions from 7 control lungs was enhanced by the addition of 2M KSCN; three of the 7 specimens showed a low degree of protease activity on heated plates. The enhancement of soluble enzyme activity in the controls indicated a direct effect of the electrolyte on enzyme activity. Hyaline membrane lungs, however, failed to develop plasminogen-activator activity in 8 of 11 supernatant fractions, and 2 of the 3 specimens that did develop lytic activity also lysed heated fibrin. It appeared, therefore, that the majority of hyaline-membrane lungs lacked saline-soluble plasminogen activator in contrast to control lungs. Acid precipitates prepared from the inactive saline extracts of hyaline membrane lungs and dissolved in 2M KSCN also lacked activator activity, in contrast to the presence of such activity in normal lungs. This finding suggested that the activator was absent from saline extracts of hyaline membrane lung rather than being merely inhibited.
It is concluded that the plasminogen activator from the lungs of human infants has no preference for human fibrin substrate over bovine or rabbit fibrin. The tissue activator of plasminogen could not be readily extracted from lung, although normal infant lung does contain a saline-soluble fraction. The activator could be soluhilized more readily in 2M KSCN, but activity was also greatly enhanced by the presence of thiocyanate or other electrolytes in high concentration. The high ionic strengths may enhance enzyme activity directly, or may reduce the effect of an inhibitor normally present in tissues. In contrast to normal lung homogenates, hyaline membrane lungs are mostly inactive against either human or bovine fibrin substrates. Plasminogen-activator activity can be manifest in hyaline membrane lungs by adding 2M thiocyanate to the lung homogenates or by extracting the lung tissue with thiocyanate. The effect of a strong inhibitor in hyaline membrane lung is apparently overcome by an increase in ionic strength or by the thiocyanate extraction procedure. By adding electrolyte to induce plasminogen-activator activity and by testing acid precipitates of saline extracts, the absence of saline-soluble plasminogen activator is shown to be the most consistent abnormality of fibrinolysis in lungs with hyaline-membranes.
Speculation: The deficiency of intrapulmonary fibrinolysis associated with pulmonary hyaline membrane formation may reflect immediate response by the organism to inflammation or stress. Inhibition of plasminogen activation within the alveolar spaces of the lung, however, may be disastrous since any retained precipitate is compressed into compact, obstructive hyaline membranes.
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Lieberman, J. Pulmonary Plasminogen-Activator Activity in Hyaline Membrane Disease: A Reevaluation on Human, Bovine, and Rabbit Fibrin Substrates. Pediatr Res 3, 11–18 (1969). https://doi.org/10.1203/00006450-196901000-00002
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DOI: https://doi.org/10.1203/00006450-196901000-00002
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