Human Meconium Has a Pulmonary Vascular and Airway Smooth Muscle Relaxant Effect

Abstract

Meconium aspiration is believed to cause persistent pulmonary hypertension syndrome of the newborn (PPHN) via vasoconstriction, whereas meconium has a relaxant effect on rat tracheal muscle. We evaluated the meconium effect on lung vascular and airway muscle. Three-days old and adult rat 3rd-4th generation arteries and adjacent bronchi were studied in vitro. Fresh homogenized meconium did not induce arterial or airway muscle contraction. In precontracted arteries, meconium induced muscle relaxation that was greater (p Ͻ 0.01) in the newborn (53 Ϯ 5%), when compared with adult vessels (34 Ϯ 3%). This relaxant response was partially abrogated (p Ͻ 0.01) by L-NAME (28 Ϯ 4%) and enhanced by a superoxide scavenger (55 Ϯ 4%). Precontracted bronchial muscle relaxed to meconium in vitro and the magnitude of response was greater in the adult when compared with the newborn (p Ͻ 0.01). In vitro incubation with meconium (3 h) reduced agonist-stimulated force and enhanced endothelium-dependent relaxation (p Ͻ 0.01). Airway meconium instillation followed by mechanical ventilation enhanced thromboxane-induced newborn rat pulmonary arterial muscle contraction in vitro (p Ͻ 0.01). We conclude that meconium is a pulmonary vasodilator in vitro MϾeconium is first noted to be present at 12 wk gestation in humans. It is the by-product of fetal amniotic fluid, lanugo, skin cells, and vernix caseosa swallowing, as well it contains cells derived from the gastrointestinal tract (1). Meconium composition also includes four different biliary acids (cholic, chenodeoxycholic, deoxycholic, and lithocholic) and minerals of which copper, zinc, magnesium, calcium iron, and phosphorus are the most common (2,3). In addition, it contains plasmatic proteins such as ␣ 1 -antitripsin and phospholipase A 2 (4,5). T he majority of infants eliminate meconium only after birth. In 15-30% of pregnancies, the fetal anal sphincter relaxes and meconium is released into the amniotic cavity prenatally (6). The factors responsible for the prenatal release of meconium are unknown. Distress either before, during labor or immediately after birth can result in meconium release and the associated gasping-like breathing activity favors its aspiration leading to a moderate to severe pneumonitis in the immediate postnatal period (6).Meconium aspiration syndrome (MAS) is often associated and further complicated by pulmonary hypertension in the neonate. The mechanism by which meconium aspiration results in the so-called persistent pulmonary hypertension syndrome of the newborn (PPHN) is presently unclear. Exposure of airway epithelial cells to meconium induces thromboxane A 2 release (7), suggesting that the MAS-associated pulmonary hypertension might be related to synthesis and/or activation of pulmonary vascular constrictor agonists.Rabbit tracheal tissue exposed to meconium in vitro shows hyperreactivity to histamine, suggesting that meconium has a direct agonist effect on the tracheal smooth muscle (8). In contrast, in vitro meconium exposure of precontracted...

L-Ornithine Derived Polyamines in Cystic Fibrosis Airways

“…Airway smooth muscle mechanical properties were measured as previously described [22], [23]. Briefly, adult C57Bl/6 mice were sacrificed, 3 rd –4 th generation intralobar bronchial segments from the left lung were mounted in a wire myograph and isometric changes were digitized and recorded (Myodaq, Danish Myo Technology A/S, Aarhus, Denmark).…”

Studies of meconium-induced lung injury: inflammatory cytokine expression and apoptosis

“…Tessler recently suggested that meconium also induced free oxygen radicals. 17 Now we describe the pathways of induction of inflammatory response following cell influx. 4 Preterm and term newborns Production of TNFa, IL1b, and IL8 is regulated by IL-10; IL-10 not detected in preterm infants with or without MAS de Beaufort et al 8 Newborn infants Overexpression of IL-8 in MAS in vitro; increased migration of neotrophils; anti-IL-8 antibodies inhibit neutrophil migration Uotila and Kaapa 9 Human monocytes In culture increase of cycloxygenase-2 expression in vitro Castellheim et al 10 Human monocytes in culture Complement activation in MAS Animal models of MAS Tyler et al 3 Animal models Surfactant inactivation, chemical pneumonitis, airway obstruction, direct toxic damage of animal lung tissues Zagariya et al 6 Rabbit pups Intense inflammatory reactions involved in meconium-induced injury in vivo; expression of endothelin 1 in MAS Davey et al 11 Piglets Acute decrease in gas exchange and dynamic lung compliance; increase of total lung protein; inhibition of surfactant Holopainen et al 12 Piglets Inflammation, airway epithelium targeted, necrotic changes, phospholipase 2 activity increased.…”

“…4 Preterm and term newborns Production of TNFa, IL1b, and IL8 is regulated by IL-10; IL-10 not detected in preterm infants with or without MAS de Beaufort et al 8 Newborn infants Overexpression of IL-8 in MAS in vitro; increased migration of neotrophils; anti-IL-8 antibodies inhibit neutrophil migration Uotila and Kaapa 9 Human monocytes In culture increase of cycloxygenase-2 expression in vitro Castellheim et al 10 Human monocytes in culture Complement activation in MAS Animal models of MAS Tyler et al 3 Animal models Surfactant inactivation, chemical pneumonitis, airway obstruction, direct toxic damage of animal lung tissues Zagariya et al 6 Rabbit pups Intense inflammatory reactions involved in meconium-induced injury in vivo; expression of endothelin 1 in MAS Davey et al 11 Piglets Acute decrease in gas exchange and dynamic lung compliance; increase of total lung protein; inhibition of surfactant Holopainen et al 12 Piglets Inflammation, airway epithelium targeted, necrotic changes, phospholipase 2 activity increased. Mollnes et al 13 Animal models Complement activation in MAS Khan et al 14 Mice Increase of IL-13 expression in MAS in vivo; lymphocytic and eosinophilic inflammation Zagariya et al 15 Rabbit pups Phospholipase A2 activates apoptosis, influx of T-lymphocytes and macrophages in vivo; increase of TNFa, IL-1b, IL-6 and IL-8 in MAS in vivo Zagariya et al 16 Rabbit pups Cell death by apoptosis, influx of neutrophils and macrophages in vivo Tessler et al 17 Newborn infants Reactive oxygen species in vitro…”

“…29 Neutrophil influx following meconium exposure may also activate alveolar macrophages to produce oxygen radicals, which may, at least in part, explain the proapoptotic effect of meconium in animal and human lungs. 17,19 Nitric oxide and apoptosis Although the bulk of evidence indicates that nitric oxide (NO) may induce apoptosis in different cell lines, including macrophages, it may have a dual effect. It is interesting to note that inhaled smaller quantities of NO may also inhibit apoptosis.…”

Constrictor Action of Substances in the Pulmonary Artery in Newborn with the Amnional Fluid Aspiration Syndrome (MAS)

“…Results of the action of histamine in pulmonary artery in our research are not in compliance with the results of the author Tessler R with bp., which ascertains that human meconium has relaxing effect in the airways smooth musculature and vascular tissue of newborn and grown rats [32].…”