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Area of Science:

  • Cell Biology
  • Biochemistry
  • Pathology

Background:

  • Tissue microenvironments in disease states like inflammation, ischemia, and tumors often exhibit metabolic acidosis.
  • Acidosis can alter cellular signaling and transcriptional activity, particularly in fibroblasts, which play a key role in tissue responses.

Purpose of the Study:

  • To investigate the impact of metabolic acidosis on rat fibroblasts.
  • To understand the role of acidosis-induced fibroblast changes in inflammation, focusing on the regulation of specific genes and signaling pathways.

Main Methods:

  • Cultured rat fibroblasts were exposed to extracellular and intracellular acidosis.
  • Gene and protein expression of TNF-α, MCP-1, COX-2, and iNOS were analyzed.
  • Activation of p38 and ERK1/2 kinases, intracellular cAMP, and calcium levels were assessed.
  • The role of Ser/Thr phosphatase activity, reactive oxygen species, and cAMP antagonism was investigated.

Main Results:

  • Extracellular acidosis enhanced TNF-α, COX-2, and iNOS expression, alongside p38 and ERK1/2 kinase activation.
  • Acidosis increased protein levels of TNF-α and COX-2, and nitrate/nitrite production.
  • COX-2 and iNOS induction depended on p38 kinase, while TNF-α induction was kinase-independent.
  • Fibroblast pH sensors GPR4, GPR68, and GPR132 were not involved; MAPK activation relied on phosphatase activity and cAMP signaling, not reactive oxygen species.

Conclusions:

  • An acidic microenvironment triggers a distinct transcriptional program in fibroblasts via the cAMP-phosphatase-MAPK pathway.
  • This process generates a pro-inflammatory state in fibroblasts, potentially leading to tissue remodeling.