Hypoxia Aggravates Inhibition of Alveolar Epithelial Na-Transport by Lipopolysaccharide-Stimulation of Alveolar Macrophages

Baloğlu E., Velineni K., Ermis-Kaya E., Mairbaeurl H.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, cilt.23, sa.15, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 23 Sayı: 15
  • Basım Tarihi: 2022
  • Doi Numarası: 10.3390/ijms23158315
  • Dergi Adı: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, CAB Abstracts, EMBASE, Food Science & Technology Abstracts, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Anahtar Kelimeler: alveolar epithelial Na-channels, Na/K-ATPase, pulmonary edema, inflammation, iNOS, hypoxia, alveolar macrophages, NITRIC-OXIDE SYNTHASE, SODIUM-CHANNEL, FLUID CLEARANCE, DECREASES EXPRESSION, TNF-ALPHA, LUNG, CELLS, EDEMA, ENAC, MODULATION
  • Acıbadem Mehmet Ali Aydınlar Üniversitesi Adresli: Evet

Özet

Inflammation and hypoxia impair alveolar barrier tightness, inhibit Na- and fluid reabsorption, and cause edema. We tested whether stimulated alveolar macrophages affect alveolar Na-transport and whether hypoxia aggravates the effects of inflammation, and tested for involved signaling pathways. Primary rat alveolar type II cells (rA2) were co-cultured with rat alveolar macrophages (NR8383) or treated with NR8383-conditioned media after stimulation with lipopolysaccharide (LPS; 1 mu g/mL) and exposed to normoxia and hypoxia (1.5% O-2). LPS caused a fast, transient increase in TNF alpha and IL-6 mRNA in macrophages and a sustained increase in inducible nitric oxide synthase (NOS2) mRNA in macrophages and in rA2 cells resulting in elevated nitrite levels and secretion of TNF-alpha and IL-6 into culture media. In normoxia, 24 h of LPS treated NR8383 decreased the transepithelial electrical resistance (TEER) of co-cultures, of amiloride-sensitive short circuit current (ISC Delta amil); whereas Na/K-ATPase activity was not affected. Inhibition was also seen with conditioned media from LPS-stimulated NR8383 on rA2, but was less pronounced after dialysis to remove small molecules and nitrite. The effect of LPS-stimulated macrophages on TEER and Na-transport was fully prevented by the iNOS-inhibitor L-NMMA applied to co-cultures and to rA2 mono-cultures. Hypoxia in combination with LPS-stimulated NR8383 totally abolished TEER and ISC Delta amil. These results indicate that the LPS-stimulation of alveolar macrophages impairs alveolar epithelial Na-transport by NO-dependent mechanisms, where part of the NO is produced by rA2 induced by signals from LPS stimulated alveolar macrophages.