The inflammatory role of platelets in cystic fibrosis.
ABSTRACT Platelets are an important, albeit generally underappreciated, component of the inflammatory cascade. Platelets are known to contribute to inflammation in atherosclerosis, stroke, and asthma. They produce a large number of proinflammatory lipid mediators and cytokines, and play a vital role in recruitment of leukocytes into inflamed tissue. We review the role of platelets in inflammation, how they assist in the recruitment of leukocytes into lung tissue in asthma, and evidence of their dysfunction in cystic fibrosis (CF). Platelet dysfunction in CF could contribute to pulmonary inflammation and tissue destruction. We hypothesize that platelet activation is important in CF lung disease and suggest research avenues that might help elucidate the role of activated platelets in CF.
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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.PLoS ONE 12/2013; 8(12):e82683. DOI:10.1371/journal.pone.0082683 · 3.53 Impact Factor
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ABSTRACT: Cystic Fibrosis (CF) represents one of a number of localized lung and non-lung diseases with an intense chronic inflammatory component associated with evidence of systemic oxidative stress. Many of these chronic inflammatory diseases are accompanied by an array of atherosclerotic processes and cardiovascular disease (CVD), another condition strongly related to inflammation and oxidative stress. As a consequence of a dramatic increase in long lived patients with CF in recent decades, the specter of CVD must be considered in these patients who are now reaching middle age and beyond. Buttressed by recent data documenting that CF patients exhibit evidence of endothelial dysfunction, a recognized precursor of atherosclerosis and CVD, the spectrum of risk factors for CVD in CF are reviewed here. Epidemiological data further characterizing the presence and extent of atherogenic processes in CF patients would seem important to interrogate. Such studies should further inform and offer mechanistic insights into how other chronic inflammatory diseases potentiate the processes leading to CVDs.Free Radical Biology and Medicine 11/2014; 76:261-277. DOI:10.1016/j.freeradbiomed.2014.08.005 · 5.71 Impact Factor
Respiration 05/2014; 88(1):22-23. DOI:10.1159/000362798 · 2.92 Impact Factor