Injurious effects of lysophosphatidylcholine on barrier properties of alveolar epithelium

Abstract

We studied the effects of lysophosphatidylcholine (lysoPC) on the barrier properties and the morphology of the alveolar-capillary membrane in isolated, fluid-filled hamster lungs continuously perfused. When instilled into the airspace at initial concentrations of 8-128 micrograms/ml, lysoPC causes dose-dependent increases in the permeability-surface area product of the alveolar epithelium for small (14C-sucrose, 342) and large (125I-neutral dextran, 70,000) solutes, with maximal values for each solute approximately 15 times control. Rapid whole-lung weight gains are caused by 128 micrograms lysoPC per milliliter, but each of the lower concentrations has no effect on net lung water balance. Electron-microscopic studies demonstrate that type I pneumonocytes are the lung cells most susceptible to lysoPC exposure, with cell swelling being the most prominent feature from low-dose exposure with more severe disruptive changes at the highest concentration tested. The effects of lysoPC are relatively specific, as several structurally related lipids have little or no effect at equivalent concentrations. Instillation of phospholipase A2 causes functional changes similar to those seen with lysoPC, presumably by generation of lysoPC from endogenous phospholipids. Studies employing a 14C-radiolabeled compound show that instilled lysoPC rapidly partitions into the lung lipid fraction where a major portion of the acyl group becomes incorporated into phosphatidylcholine. The amount of instilled lysoPC required to produce functional and morphological effects comprises only a few percent of total lung phospholipids. Since lysoPC is a normal component of lung phospholipids, severe lung dysfunction might result from minor abnormalities in the formation or degradation of this compound.

In vitro secretion kinetics of proteins from Legionella pneumophila in comparison to proteins from non-pneumophila species

“…Enrichment of LPC occurred when PLA activity was high in comparison to LPLA activity and\or when LPLA was secreted in a delayed manner. LPC is known to contribute to induction of inflammation, impairment of lung function, cytotoxicity, pore formation and signal transduction (Aronson & Johns, 1977 ;Dennis, 1997 ;Flieger et al, 2000b ;Holm et al, 1991 ;Kume et al, 1992 ;Lindahl et al, 1986 ;Niewoehner et al, 1987 ;Prokazova et al, 1998 ;Weltzien, 1979). Accumulation of LPC could therefore trigger important mechanisms in the development of Legionnaires' disease.…”

Cell envelope constituents of Pseudomonas putida contributing to growth and survival in low-water-content habitats

“…We also show that lysophospholipids (phospholipids that have only one of two fatty acyl chains) accumulate to higher levels in wdc200 than LH0001, especially when grown under water-limited conditions. Moreover, we show that addition of exogenous lysophospholipids and the disruption of PP2318 impair bacterial fitness, which is congruent with previous reports that lysophospholipids are toxic (Weltzien, 1979;Niewoehner et al, 1987;Flieger et al, 2002). These results indicate that PP2318 likely functions as a lysophospholipase, which is involved in removing lysophospholipids or preventing their formation.…”

“…Presumably, LPL are toxic and lysophospholipases remove LPL by degrading them to the glycerol backbone and free fatty acid (Weltzien, 1979;Niewoehner et al, 1987;Garsetti et al, 1992;Flieger et al, 2002). To assess whether LPL are toxic to P. putida we exposed surface-grown cells cultured on PEGSOOO-amended medium to exogenously supplied LPG and determined culturability over time.…”

“…Moreover, we found that wdc200 exhibited significantly poorer survival after LPG exposure than LH0001, suggesting that loss of PP2318 rendered wdc200 more sensitive to LPG toxicity. Presumably, exogenous LPL are rapidly incorporated into the membrane bilayer (Niewoehner et al, 1987) and incorporation of even a relatively small amount of these 'wedge-shaped' molecules into the phospholipid bilayer induces excessive curvature of the planar membrane structure (Weltzien, 1979), leading to disruptive membrane changes (Niewoehner et al, 1987) and leakage (Lee and Chan, 1977;Weltzien, 1979;Lindahl et al, 1986). Insertion of LPL may also cause a redistribution of charges within the membrane and redistribute membrane proteins thereby changing their activity (Lumper et al, 1970).…”

Pathogenese der Legionelleninfektion

“…Es ist daher von Interesse, die Beteiligung weiterer Typ-II-sekretierter Legionella-Proteine an der intrazellulä-ren Replikationsfähigkeit von Legionellen näher zu untersuchen sowie neue sekretierte Effektoren aufzufinden. [26,27]. Zusätzlich konnten wir zeigen, dass der Abbau an SurfactantDiazylphospholipiden und die Anreicherung von Lysophosphatidylcholin zur Verschlechterung der physikalischen Eigenschaften des Lungensurfactants führt, die für die Lungenfunktion notwendig sind [37].Mit diesen Experimenten konnte zum ersten Mal die häufig beobachtete Ausprägung von ARDS und erhöhtem Atemwiderstand bei Patienten mit Legionellenpneumonie erklärt werden [37].…”