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Cystic Fibrosis (Lung Biology in Health and Disease)
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Stay on CRCPress. Exclusive web offer for individuals on all book. Preview this Book. Cystic Fibrosis 1st Edition Julian L. Allen, Howard B. Panitch, Ronald C. Add to Wish List. Close Preview. Toggle navigation Additional Book Information. Description Table of Contents. Summary The median age of survival for those with cystic fibrosis has risen considerably in recent years. Request an e-inspection copy. Share this Title.
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View Cart. It has been suspected that platelets can undergo differential granule release of pro- or anti-inflammatory mediators depending on specific circumstances. Histamine and serotonin increase vascular permeability; ADP increases the agonist-induced oxidative burst in PMN; platelet-derived growth factor PDGF stimulates chemotaxis for monocytes and primes eosinophils to produce superoxide anion; and, PF4 induces PMN to adhere to unstimulated vascular endothelium, induces the release of histamine from basophils, and stimulates the adherence of eosinophils to vascular walls.
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Platelets metabolize arachidonic acid AA via the cyclooxygenase and lipoxygenase pathways to produce inflammatory mediators, the most abundant of which are TXA 2, via the cyclooxygenase pathway, and S-HETE, via the lipoxygenase pathway. Platelets also provide positive feedback mechanisms for their own activation. ADP secreted from dense granules and TXA 2 formed from AA bind to P2Y and TP receptors on the platelet surface, complete initial platelet activation, and recruit additional platelets into the activated fraction.
Thus, once the inflammatory cascade has been initiated, leukocytes and platelets combine to propagate and amplify it. In addition to the active role platelets play in producing inflammatory mediators — and perhaps even more important — is the role they play in the process of migration of WBC from the vascular compartment to the site of tissue injury or inflammation.
In order for leukocytes to invade inflamed or infected tissue, the white blood cell must first be tethered to the vessel wall and roll along the endothelial surface, then attach firmly to the endothelium, and finally migrate through the endothelium into the tissue. However, tethering and rolling are dependent upon the function of selectins, especially P-selectin.
Although endothelial expression of P-selectin alone can lead to leukocyte rolling, this process which is a necessary precursor to firm attachment and diapedesis is much more efficient in the presence of platelet P-selectin in part due to platelet-leukocyte aggregates which amplify the ability of WBC to be recruited to the endothelial surface by cross-linking figure 1. The number of platelets adherent to pulmonary vessels the marginated pool need not be large in order to affect vascular permeability and PMN recruitment. A small number of activated platelets can signal PMN-platelet and platelet-platelet interactions that lead to an increased number of platelet-PMN aggregates, which can become tethered to the pulmonary vascular endothelium.
Megakaryocytes are found in human lung microvessels and may spawn platelets and platelet precursors in this location. Reproduced from Weyrich and Zimmerman Platelets in Lung Biology. Thus, platelets fit the definition of traditional inflammatory cells in many ways -- they are capable of phagocytosis and elaboration of pro-inflammatory cytokines, chemokines, and lipid mediators, and are vital for the process of leukocyte tethering and rolling, which are necessary fist steps in recruitment of leukocytes to areas of inflammation. Animals made deficient in platelets or in whom platelet P-selectin is blocked or deficient are less capable of mounting an inflammatory response and have fewer white blood cells in target organs and humans with inflammatory processes have increased numbers of platelet-leukocyte aggregates and increased expression of platelet P-selectin, both markers of platelet activation.
In addition to the pro-inflammatory properties of platelets outlined above, these tiny blood constituents are essential effector cells in lung hemorrhage and in vascular barrier function. As reviewed by Weyrich and Zimmerman, platelets play at least 5 roles in maintaining endothelial barrier function in the pulmonary circulation: release of soluble molecules that enhance barrier function, physical obstruction of gaps, maintenance of structural features of endothelial cells, stimulation of endothelial growth, and neutralization of agents that might enhance endothelial permeability.
Among the secreted products that enhance endothelial cell-cell interactions and promote vascular integrity are shingosinephosphate S1P , serotonin, and angiopoietin S1P appears to be particularly important in stabilizing pulmonary endothelium by enhancing adherens junctions and tight junctions.
Platelets are also important for vascular repair and remodeling. The vasoactive substances that platelets release may play protective or damaging roles depending on the circumstances surrounding platelet activation. Platelets are active effector cells in wound healing and can also play roles in angiogenesis and vascular repair and remodeling. Platelet activation leading to airway inflammation. Over a century ago Sir William Osler recognized that asthma was an inflammatory disease.
Much work has been done since then looking for causes and treatments of airway inflammation in patients with asthma. In a series of elegant animal and human experiments spanning more than a decade, investigators have shown that platelets play a fundamental role in the recruitment of leucocytes to the lungs following exposure to allergens and play a key role in the onset and perpetuation of airway inflammation in asthma. Following this work, Ulfman and colleagues[ 39 ] showed that P-selectin bearing platelets were integral in tethering of eosinophils to activated endothelium in an ex-vivo perfusion model.
Further studies have shown the importance of platelet P-selectin and soluble P-selectin in eosinophil attachment to VCAM Platelets also appear to play a role in causing disease in the lung parenchyma itself, with evidence of platelet diapedesis into lungs in animals sensitized to allergens. Reproduced from Mattosccio et al.
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Human studies substantiate the finding of the importance of platelets seen in allergic animal models. There is a decreased half-life of platelets in atopic patients, implying increased platelet activation and turnover. Moritani and colleagues[ 42 ] were able to demonstrate an association between platelet activation as assessed by P-selectin expression and RANTES release with an asthmatic diathesis in humans.
Similarly, Durk and colleagues[ 43 ] have shown increased serotonin in segmental lavage fluid from asthmatic subjects when challenged locally, implying a role for activated platelets, the major source of serotonin in the human lung, in allergic inflammation. These authors suggest that peripheral serotonin production could be a viable target for future asthma therapy.
Cystic Fibrosis Symptoms, Causes & Risk Factors
Others have shown a temporal relationship between circulating platelet-derived factors included soluble P-selectin and early and late asthmatic response in allergic subjects. Lommatzsch, et al[ 10 ] have looked at another, less well-studied platelet secretion, brain-derived neurotrophic factor BDNF. This group found that patients with asthma had higher levels of BDNF in serum, platelets, and plasma compared to non-asthmatic matched controls.
BNDF levels correlated with parameters of airway obstruction and hyper-reactivity, making this mediator of neuronal plasticity one more platelet product capable of affecting the asthmatic airways. Associations between platelets and metabolites of arachidonic acid have been identified in asthma patients.
Lipoxins play a role in the resolution phase of inflammation and are the product of interaction between PMN-associated arachidonic acid and platelet-derived lipoxygenase. Oxidative stress in asthma is correlated with decreased LXA 4 in patients with severe asthma and reflects a loss of anti-inflammatory balance in these patients. In this group of patients ex-vivo incubation of cells with an inhibitor of LX degradation significantly inhibited the PAF-induced platelet-leukocyte aggregates in peripheral blood that contribute to persistent airway inflammation.
Platelet-leukocyte interactions in respiratory endothelium in acute lung Injury. Platelet activation upregulates adhesion molecules. B Platelets and PMN accumulation in microvasculature is enhanced by fibrin deposition in response to enodthelial injury. C Platelets facilitate accumulation of PMN in alveoli and interstitial spaces and contribute to alveolar leak syndromes.
In a series of human studies specifically looking at aspirin exacerbated respiratory disease, examination of nasal polyps from aspirin sensitive subjects demonstrated extravascular platelets adjacent to leukocytes. Platelets appeared to contribute an inordinate amount of LTC 4 synthase activity in these subjects compared to non-aspirin sensitive subjects. Further mouse studies by this group have shown a potential role for anti-platelet drugs in aspirin induced asthma.
Reduced production of melatonin by platelets also has been seen in aspirin-sensitive asthmatics. It is possible that the coagulation cascade may also play a role in the airway remodeling seen in chronic asthmatic patients. Growing evidence in human and non-human models clearly makes this a promising area to pursue. Cystic fibrosis CF is an autosomal-recessive illness that is the most common lethal inherited disease in the Caucasian population. CF is caused by a mutation in the cystic fibrosis transmembrane conductance regulator CFTR gene on the long arm of chromosome 7.
Loss of chloride channel function leads to dehydration of the airway surface liquid, which leads to thickened airway secretions, chronic respiratory infection, neutrophilic lung infection, pulmonary destruction, and premature death. The CFTR protein acts predominantly as a chloride channel, but plays multiple other roles in cellular metabolism, including influencing long chain fatty acid synthesis. This inflammatory process is characterized by PMN infiltration of airways and pulmonary parenchyma with elaboration of free neutrophil elastase and pro-inflammatory cytokines.
By the end of the s a number of studies had been performed assessing the function of platelets from CF patients. These studies were done prior to the discovery of the CFTR gene and with an incomplete understanding of the underlying molecular defect in these patients. A better picture of the role of platelets in CF has emerged with improved techniques for evaluating platelet function and a more complete knowledge of CFTR function. These studies have shown that: 1 increased platelet numbers correlate with decreased arterial blood oxygen tension P a O 2 ,[ 52 ] 2 an increase in urinary concentration of thromboxane metabolites a marker of platelet activation in vivo correlates with decreased forced expiratory volume FEV 1 ,[ 53 , 54 ] and 3 increased plasma concentrations of soluble CD40 ligand sCD40L.
Several groups have demonstrated increased reactivity of CF platelets. Ciabattoni and colleagues[ 54 ] showed enhanced lipid peroxidation, which contributes to platelet activation in CF patients.
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They documented increased urinary excretion of TxB 2 metabolites and isoprostanes, consistent with oxidative stress and increased arachidonic acid turnover in CF patients and hypothesized that these factors led to platelet aggregation and activation and contributes to lung disease in CF patients. Also, platelets from CF patients incubated in plasma from non-CF subjects were more reactive to agonists than control platelets in the same plasma. This observation was critical as platelet dense granules contain many mediators responsible for the recruitment of inflammatory cells. Thus CF patients may have a muted inflammatory cell mobilization.
CFTR protein expression was first described in epithelial cells from nasal epithelium and sweat glands in humans. It is feasible that platelets also express CFTR and that its absence might explain some of the abnormalities in platelet function seen in CF patients. Agam et al. In another indirect evaluation of CFTR function in CF platelets, Ulane and collaborators [ 59 ] demonstrated an intrinsic increase in turnover of platelet membrane phospholipids specifically, phosphatidylcholine , which they ascribed to CFTR dysfunction. Elegant studies by this group on CF platelet proteomics has shown distinct characteristics of CF platelets that predispose them to promoting pulmonary inflammation.
Platelets have been found to contain an excess of the long-chain polyunsaturated fatty acid known as Mead acid. CF patients have a defect in lipoxin synthesis that appears to be directly related to a lack of normal function of CFTR in platelets. Furthermore, cells from respiratory epithelium of CF patients have a decreased amount of another long chain polyunsaturated fatty acid, docosahexaenoic acid DHA. It appears that when normal CFTR function is lost in those with CF results in patients with CF it results in upregulation of inflammation and a corresponding loss of the counterbalancing resolution phase of inflammation.
In fact, there is evidence that platelets from non-CF subjects are activated when incubated in CF plasma. In summary, loss of normal CFTR function can indirectly increase platelet activation through its affect on plasma factors such as specific cytokines, fatty acids, ATP, and vitamin E, and loss of CFTR function specifically in platelets can directly increase platelets activation.
The final result, irrespective of cause of activation, is increased recruitment and activation of leukocytes into the CF lung, elaboration of mediators that cause tissue damage, and enhanced loss of lung function. The acute respiratory distress syndrome ARDS is defined as acute onset of hypoxemia in response to insults including sepsis, trauma, aspiration, and toxins. In the American-European Consensus Conference defined ARDS as acute onset of hypoxemia with bilateral infiltrates on chest roentgenogram and no evidence of left atrial hypertension.
A hallmark of ARDS is increased capillary leak and influx of neutrophils and fluid into the lung interstitium. Recent reviews have emphasized the role of platelets in instigating this pulmonary vascular leak.
The interplay between coagulation and inflammation has become an increasingly active area of investigation in acute lung injury. The maintenance of a normal endothelial cell barrier is a critical component of the fluid and protein diffusion balance in the pulmonary circulation. In health, platelets play an important role in systemic and pulmonary vascular integrity see above.
A number of studies show that platelet depletion can lead to vascular leakage and that reconstitution with infused platelets can correct the barrier defect reviewed in reference 1. Platelets may take up radical oxygen species and release preformed mediators such as serotonin, which contribute to endothelial barrier stability.