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  • Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation.

Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation.

The Journal of clinical investigation (2020-01-22)
Guadalupe Ortiz-Muñoz, Michelle A Yu, Emma Lefrançais, Beñat Mallavia, Colin Valet, Jennifer J Tian, Serena Ranucci, Kristin M Wang, Zhe Liu, Nicholas Kwaan, Diana Dawson, Mary Ellen Kleinhenz, Fadi T Khasawneh, Peter M Haggie, Alan S Verkman, Mark R Looney
ABSTRACT

Cystic fibrosis (CF) lung disease is characterized by an inflammatory response that can lead to terminal respiratory failure. The cystic fibrosis transmembrane conductance regulator (CFTR) is mutated in CF, and we hypothesized that dysfunctional CFTR in platelets, which are key participants in immune responses, is a central determinant of CF inflammation. We found that deletion of CFTR in platelets produced exaggerated acute lung inflammation and platelet activation after intratracheal LPS or Pseudomonas aeruginosa challenge. CFTR loss of function in mouse or human platelets resulted in agonist-induced hyperactivation and increased calcium entry into platelets. Inhibition of the transient receptor potential cation channel 6 (TRPC6) reduced platelet activation and calcium flux, and reduced lung injury in CF mice after intratracheal LPS or Pseudomonas aeruginosa challenge. CF subjects receiving CFTR modulator therapy showed partial restoration of CFTR function in platelets, which may be a convenient approach to monitoring biological responses to CFTR modulators. We conclude that CFTR dysfunction in platelets produces aberrant TRPC6-dependent platelet activation, which is a major driver of CF lung inflammation and impaired bacterial clearance. Platelets and TRPC6 are what we believe to be novel therapeutic targets in the treatment of CF lung disease.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-15, ascites fluid
Sigma-Aldrich
CFTR Inhibitor-172, CFTR Inhibitor-172, CAS 307510-92-5, is a cell-permeable, potent, reversible, rapid, and voltage-independent inhibitor of CFTR-mediated Cl- transport in human airway cells (Ki ~ 300 nM).
Large Column Holder, For columns o.d. 50 mm, ÄKTA®xpress, Cytiva 28400737