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40 Pulmonary artery fibroblasts in sleep disordered breathing conditions: increased proliferation and discovery of humoral factors eliciting p38 MAPK kinase proliferation
  1. R Timoney,
  2. K Suveizdyte,
  3. C Carlin,
  4. DJ Welsh
  1. University of Glasgow, UK

Abstract

Introduction Obstructive Sleep Apnoea (OSA) and Obesity Hypoventilation Syndrome (OHS) are sleep breathing disorders (SBD); respectively characterised by nocturnal intermittent hypoxaemia, and sustained hypoxaemia. Studies of pulmonary hypertension have found pulmonary arterial fibroblasts to proliferate excessively in hypoxic conditions due to activation of the p38MAPK pathway.

Aims i) Determine if an elevated proliferative response occurs in various degrees of intermittent hypoxia. ii) To explore the presence of humoral factors in SDB patient serum that stimulate p38 MAPK activation.

Methods Rat pulmonary arterial fibroblasts (RPAFs) were exposed to contrasting levels of hypoxia/normoxia in bovine serum. RPAF cell division was quantified via [3H] Thymidine proliferation assays. Western Blot analysis, for total and phospho-p38 MAP kinase, was undertaken in RPAFs exposed to 24 h of normoxia and patient serum.

Results 8 h of hourly intermittent or sustained acute hypoxia followed by 16 h of normoxia triggered elevated RPAF proliferation, similar to 24 h of acute hypoxia. In contrast, no increase in RPAF proliferation was seen with 18 h of normoxia followed by 6 h of hypoxia. Exposure of RPAFs to OHS patient serum elicited a signficant increase in pp38 MAPK vs control and OSA serum; this was reduced in serum taken post treatment.

Conclusion Conditions mimicking SBD elicit hyper-proliferative responses in RPAFs. This study has questioned the existence of a vulnerable point within the cell cycle to which hypoxia will elicit fibroblast proliferation. The differences in RPAF p38 activation by OSA/OHS patient serum, including evidence of an early treatment effect, indicate pathogenic pathways.

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