Abstract
Mutation of CFTR (cystic fibrosis transmembrane conductance regulator) leads to cystic fibrosis (CF). Patients with CF develop abnormalities of blood platelets and recurrent lung inflammation. However, whether CFTR-mutated platelets play a role in the development of lung inflammation is elusive. Therefore, we intratracheally challenged wildtype and F508del (a common type of CFTR mutation) mice with LPS to observe changes of F508del platelets in the peripheral blood and indexes of lung inflammation (BAL neutrophils and protein levels). Furthermore, we investigated whether or not and how F508del platelets modulate the LPS-induced acute lung inflammation by targeting anti-platelet aggregation, depletion of neutrophils, reconstitution of bone marrow or neutrophils, blockade of P-selectin glycoprotein ligand-1 (PSGL-1), platelet activating factor (PAF), and correction of mutated CFTR trafficking. We found that LPS-challenged F508del mice developed severe thrombocytopenia and had higher levels of plasma TXB2 coincided with neutrophilic lung inflammation relative to wildtype control. Inhibition of F508del platelet aggregation or depletion of F508del neutrophils diminished the LPS-induced lung inflammation in the F508del mice. Moreover, wildtype mice reconstituted with either F508del bone marrow or neutrophils developed worse thrombocytopenia. Blocking PSGL-1, platelet activating factor (PAF), or rectifying trafficking of mutated CFTR in F508del mice diminished and alveolar neutrophil transmigration in the LPS-challenged F508del mice. These findings suggest that F508del platelets and their interaction with neutrophils are requisite for the development of LPS-induced lung inflammation and injury. As such, targeting platelets might be an emerging strategy for dampening recurrent lung inflammation in cystic fibrosis patients.
Highlights
Recurrent inflammatory lung disease is a leading cause of morbidity and mortality in cystic fibrosis (CF), which are previously attributed to CFTR defect in the epithelial cells
Lung inflammation was severe in F508del mice relative to the wildtype reflected by more neutrophils present in the Bronchoalveolar lavage (BAL) (Figure 1 C–E) and higher BAL protein levels
Attenuation of thrombocytopenia by inhibiting platelet aggregation, depleting F508del neutrophils, blocking P-selectin glycoprotein ligand-1 (PSGL-1) or platelet activating factor (PAF), or rectifying of F508del CFTR trafficking in LPS-challenged F508del mice significantly diminished neutrophil transalveolar migration or lung inflammation
Summary
Recurrent inflammatory lung disease is a leading cause of morbidity and mortality in cystic fibrosis (CF), which are previously attributed to CFTR defect in the epithelial cells. Recent studies have demonstrated that mutation of cftr in non-epithelial cells, for example, neutrophils and platelets, contributes to the exaggerated proinflammatory responses of CF [1,2]. Inhibition of CFTR in platelets increased phosphorylation of p38MAPK [2], and the latter propagates platelet-neutrophil interaction. Platelets can interact with neutrophils through P-selectin glycoprotein ligand-1 (PSGL-1) [8] or platelet activating factor (PAF) [9] to elicit platelet aggregation, thrombocytopenia, and inflammation. Under CFTR dysfunction, the role of platelets in modulating lung inflammation has not been validated by the animal experiments
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