Abstract
The alveolar epithelial cells represent an important part of the alveolar barrier, which is maintained by tight junction proteins, particularly JAM-A, occludin, and claudin-18, which regulate paracellular permeability. In this study, we report on a strong increase in epithelial JAM-A expression in P2X7 receptor knockout mice when compared to the wildtype. Precision-cut lung slices of wildtype and knockout lungs and immortal epithelial lung E10 cells were treated with bleomycin, the P2X7 receptor inhibitor oxATP, and the agonist BzATP, respectively, to evaluate early changes in JAM-A expression. Biochemical and immunohistochemical data showed evidence for P2X7 receptor-dependent JAM-A expression in vitro. Inhibition of the P2X7 receptor using oxATP increased JAM-A, whereas activation of the receptor decreased the JAM-A protein level. In order to examine the role of GSK-3β in the expression of JAM-A in alveolar epithelial cells, we used lithium chloride for GSK-3β inhibiting experiments, which showed a modulating effect on bleomycin-induced alterations in JAM-A levels. Our data suggest that an increased constitutive JAM-A protein level in P2X7 receptor knockout mice may have a protective effect against bleomycin-induced lung injury. Bleomycin-treated precision-cut lung slices from P2X7 receptor knockout mice responded with a lower increase in mRNA expression of JAM-A than bleomycin-treated precision-cut lung slices from wildtype mice.
Highlights
Alveolar epithelial cells (AEC) represent the most vulnerable cells of the distal lung parenchyma and consist of flat AECI type I and cuboidal AECII type II cells in most vertebrates, including humans
We further studied the influence of BLM on junctional adhesion molecules (JAM)-A in precision-cut lung slices (PCLS) of WT and P2X7−/− mice and in immortal AECI-like E10 cells and whether the glycogen synthase kinase (GSK)-3β(Ser9) phosphorylation changed after BLM treatment
Maintenance of the integrity of the alveolar barrier is realized by tight junctions (TJ) among neighboring AECs consiMstianigntoefnoacnccleudoifnt,hcelaiundteignrsi,tyZOofs,thanedalJvAeMol-aAr .barrier is realized by TJ among neighboring AECs consiRseticnegntolfy,owcceluhdaivne, dcleamudoninsstr, aZtOeds,thanatdinJAPM2X-A7−./− mice, claudin-18 is upregulated and the inactive formRoefcGenStKly,3wβ,eGhaSvKe-3dβe(mSeorn9s)t,raisteadlstohautpinrePg2uXla7t−e/−dminicec,ocmlapuadriins-o1n8 tios uWprTegmuilcaete[d12a]n. dOthuer icnuarcrteivnet dfoartma sohfoGwSKth-a3tβ,aGnoStKh-e3rβT(SJepr9ro),teisina,lsJoAuMp-rAeg, uinlaPte2dX7in−/c−ommipcaeriissosntrtoonWglyT umpirceeg[u12la].teOduartctuhrerepnrtodteaitna level
Summary
Alveolar epithelial cells (AEC) represent the most vulnerable cells of the distal lung parenchyma and consist of flat AECI type I and cuboidal AECII type II cells in most vertebrates, including humans. To maintain cellular polarity and barrier functions of AEC, several types of intercellular junctions exist such as tight junctions (TJ), adherens junctions (AJ), gap junctions, and desmosomes. TJ proteins are important in the regulation of the transcellular permeability of AEC. Besides their completely different morphological appearance, AECI and AECII differ in their protein pattern, which allows, to a certain degree, their distinction from each other [3]. In the most distal part of lung, P2X7R is selectively present in AECI [9] and in alveolar macrophages [10]. The intracellular pathways activated by the receptor influence pulmonary inflammation (reviewed in Reference [11]) and the P2X7R knockout (P2X7−/−) lung show altered tight junction protein expression [12]
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