Editors' ChoiceCystic Fibrosis

The sticky culprit: Platelets in cystic fibrosis

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Science Translational Medicine  15 Apr 2020:
Vol. 12, Issue 539, eabb5670
DOI: 10.1126/scitranslmed.abb5670


Platelets trigger lung inflammation in cystic fibrosis.

Cystic fibrosis (CF) is a chronic and progressive disorder that involves multiple organ systems and is caused by mutation in the CFTR gene. Historically, CFTR deletion has been deemed responsible for the production of thick mucus, abnormal airway clearance, and recurrent infection, which lead to bronchiectasis and eventually terminal respiratory failure. However, there is now emerging evidence that lung inflammation may be a primary abnormality rather than a secondary phenomenon in driving the pathophysiology associated with CF lung disease.

In this study, Ortiz-Munoz et al. investigated the role of platelets in causing lung inflammation in CF. They hypothesized that platelet activation could be a primary event responsible for the ongoing inflammation and neutrophil-mediated injury in CF. They first demonstrated increased lung inflammation in Cftr–/– mice in response to LPS as well as Pseudomonas infection (a common pathogen in patients with CF). Thereafter, they used mice with tissue specific Cftr deletion in the entire myeloid lineage, only in the neutrophils or only in the platelets. They found that the mice with platelet specific Cftr deletion had increased lung inflammation as well as bacterial load compared with the other experimental groups. Further they found evidence of more neutrophil-platelet and monocyte-platelet aggregates in the platelet-specific Cftr–/– but not in the neutrophil-specific knockout. In addition, they investigated the pathway mediating the increased disease severity using a combination of in vivo and in vitro experiments and showed that the calcium channel Transient Receptor Potential Cation Channel Subfamily C Member 6 (Trpc6) was responsible for the increased inflammation. The investigators also compared platelets obtained from healthy controls and patients with CF and showed, as proof of concept, that the platelets from patients were in a state of higher activation.

Although acute inflammation has been well characterized in this study, it would have been interesting to study the effects of platelet specific Cftr deletion on lung pathology, in particular determining bronchiectasis-like changes that characterize CF lung disease. However, even if the results remain limited to mediating acute inflammation, the present study does provide provocative potential adjuvant therapy options for this debilitating disease. Platelets have been targeted in many disease conditions, and the translational relevance of this study lies in providing us the mechanistic justification to repurpose some of these drugs for CF.

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