Characterization of serine/cysteine protease inhibitor α₁‐antitripsin from meconium‐instilled rabbit lungs

Abstract

We have recently purified from meconium-instilled rabbit lungs a novel serine proteinase inhibitor, with an apparent molecular mass of 50 kDa, which we assign to be alpha1-antitripsin. We hypothesize that serpin may attenuate pulmonary inflammation and improve surfactant function after meconium aspiration. Alpha1-antitripsin is a member of the proteinase inhibitor (serpin) superfamily and inhibitor of neutrophil elastase, and it can be identified as a member of the family by its amino acid sequence due to the high degree of conserved residues. Alpha1-antitripsin is synthesized by epithelial cells, macrophages, monocytes, and neutrophils. Deficiency in alpha1-antitripsin leads to exposure of lungs to uncontrolled proteolytic attack from neutrophil elastase or other damaging factors culminating in lung destruction and cell apoptosis. We hypothesize that accumulation of alpha1-antitripsin in the lungs serves as a predisposed protection against meconium-induced lung injury. In this paper, we show how this knowledge can lead to the development of novel therapeutic approaches for treatment of MAS.

Inflammation in Meconium Aspiration Syndrome: Targets for Pharmacological Modulation

“…Serine elastase inhibitors administered in severe monocrotaline-induced pulmonary vascular disease reduced pulmonary artery pressure, muscularization, and extracellular matrix (elastin and tenascin C), and improved survival [169]. It is supposed that increased levels of -1 protease inhibitors in the lungs may serve as a protection against proteolytic attack of neutrophil elastase also in meconium-induced lung injury [170].…”

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

“…We found that this protein to be a novel serine proteinase inhibitor, with an apparent molecular mass of 50 kDa, which was identified to be e a1-antitripsin. 39 Serpins are known inhibitors of proteases and apoptosis. We hypothesize that serpin may attenuate pulmonary inflammation and improve surfactant function after meconium aspiration.…”

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

“…Composition of amniotic fluid is also quite heterogenic by mentioning here different tissue cells [22], plasmatic proteins (α 1 -antitripsin and phospholipase A 2, [23,24], different biliar acids and different minerals such calcium salts, magnesium, zinc, and copper [25].…”

“…choline, chenodeoxycholic and lithocholic acid) and minerals such copper, zinc, manganese, calcium, iron, and phosphorus as most often ones [5,6]. Continuously, it contains plasmatic proteins (alpha-1 antitrypsin) [7,8]. Meconium is also composed of other different substances such interleukins IL-1ß, IL-6 and IL8, necrotizing tumoral factor (TNFalpha) [9] and phospholipases A 2 (PLA 2 ) [10] that might induce direct and indirect pulmonary inflammation by increasing the production of cytokines and by activating leukocytes or epithelial and endothelial cells of the lung.…”