The Inflammatory Role of Platelets in Cystic Fibrosis

Department of Pediatrics, UMass Memorial Health Care, 55 Lake Avenue, North Worcester, MA 01655, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 04/2006; 173(5):483-90. DOI: 10.1164/rccm.200508-1243PP
Source: PubMed


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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    • "Inhibition of CFTR in platelets increased phosphorylation of p38MAPK [2], and the latter propagates platelet-neutrophil interaction. In CF patients, circulating leukocyte-platelet aggregates might be related to the progression of the lung inflammation [3–5], and treatment with high-dose ibuprofen (anti-platelet aggregation) in CF patients improved lung function in the CF patients [6–7]. 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. "
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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 · 3.23 Impact Factor
    • "There were a number of studies demonstrating that the patients with CF had an increased number of circulating platelets,[10] increased platelet activation as a response to gram negative infection,[11] and increased urinary tromboxane excretion correlated with decreased FEV1.[12] These studies suggested that in cystic fibrosis, the mediators secreted by platelets for leucocyte recruitment also activated themselves causing a positive feedback loop, which had a potential risk for lung disease exacerbation and progressive pulmonary damage.[13] "
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    ABSTRACT: The aim of this study is to evaluate the relationship between acute exacerbations and the mean platelet volume (MPV) trend in children with cystic fibrosis (CF), to predict the exacerbations. A total of 46 children with CF and 37 healthy children were enrolled in the study. White blood cell count (WBC), hemoglobin level, platelet count, mean platelet volume (MPV), and mean corpuscular volume (MCV) were retrospectively recorded. Our study population consisted of 25 (54.3%) males and 21 (45.7%) females with CF and 20 (54.0%) males and 17 (46.0%) females in the healthy control group. The mean age of the CF patients was 6.32 ± 4.9 years and that of the healthy subjects was 7.02 ± 3.15 years. In the acute exacerbation period of CF, the MPV values were lower and WBC and platelet counts were higher than those in the healthy controls (P = 0.00, P = 0.00, P = 0.00, respectively). Besides, in acute exacerbation, the MPV values were lower and the WBC count was higher than the values in the non-exacerbation period (P 0= 0.01, P = 0.00, respectively). In the non-exacerbation period MPV was lower and platelet count was higher when compared to healthy subjects (P = 0.02, P = 0.04, respectively). This study suggests that MPV might be used as a simple, cost effective, diagnostic, predictive indicator for platelet activation in pediatric CF patients related to chronic inflammation, which might be helpful to discriminate or estimate exacerbations.
    03/2011; 6(4):227-30. DOI:10.4103/1817-1737.84778
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    • "A third hypothesis for SWCNT exposure–mediated cardiovascular effects is through platelet activation in the lung circulation . The pulmonary circulation is considered a site for platelet formation (Martin et al. 1983; O'Sullivan and Michelson 2006), and it has been demonstrated that SWCNT can directly activate platelet aggregation in vitro (Radomski et al. 2005). Furthermore, transforming growth factor-β1(TGF−β1), which is involved in platelet activation (Hoying et al. 1999), has been found to be significantly increased in the lung of SWCNT-treated mice (Shvedova et al. 2005), and the time course of its increase paralleled the occurrence of cardiovascular mitochondrial dysfunction. "
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    ABSTRACT: Engineered nanosized materials, such as single-wall carbon nanotubes (SWCNT), are emerging as technologically important in different industries. The unique physical characteristics and the pulmonary toxicity of SWCNTs raised concerns that respiratory exposure to these materials may be associated with cardiovascular adverse effects. In these studies we evaluated aortic mitochondrial alterations by oxidative stress assays, including quantitative polymerase chain reaction of mitochondrial (mt) DNA and plaque formation by morphometric analysis in mice exposed to SWCNTs. A single intrapharyngeal instillation of SWCNTs induced activation of heme oxygenase-1 (HO-1), a marker of oxidative insults, in lung, aorta, and heart tissue in HO-1 reporter transgenic mice. Furthermore, we found that C57BL/6 mice, exposed to SWCNT (10 and 40 mug/mouse), developed aortic mtDNA damage at 7, 28, and 60 days after exposure. mtDNA damage was accompanied by changes in aortic mitochondrial glutathione and protein carbonyl levels. Because these modifications have been related to cardiovascular diseases, we evaluated whether repeated exposure to SWCNTs (20 mug/mouse once every other week for 8 weeks) stimulates the progression of atherosclerosis in ApoE(-/-) transgenic mice. Although SWCNT exposure did not modify the lipid profiles of these mice, it resulted in accelerated plaque formation in ApoE(-/-) mice fed an atherogenic diet. Plaque areas in the aortas, measured by the en face method, and in the brachiocephalic arteries, measured histopathologically, were significantly increased in the SWCNT-treated mice. This response was accompanied by increased mtDNA damage but not inflammation. Taken together, the findings are of sufficient significance to warrant further studies to evaluate the systemic effects of SWCNT under workplace or environmental exposure paradigms.
    Environmental Health Perspectives 04/2007; 115(3):377-82. DOI:10.1289/ehp.9688 · 7.98 Impact Factor
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