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Inflammatory Lung Diseases (inflammatory + lung_disease)
Selected AbstractsProtease-activated receptors and prostaglandins in inflammatory lung diseaseBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2009Terence Peters Protease-activated receptors (PARs) are a novel family of G protein-coupled receptors. Signalling through PARs typically involves the cleavage of an extracellular region of the receptor by endogenous or exogenous proteases, which reveals a tethered ligand sequence capable of auto-activating the receptor. A considerable body of evidence has emerged over the past 20 years supporting a prominent role for PARs in a variety of human physiological and pathophysiological processes, and thus substantial attention has been directed towards developing drug-like molecules that activate or block PARs via non-proteolytic pathways. PARs are widely expressed within the respiratory tract, and their activation appears to exert significant modulatory influences on the level of bronchomotor tone, as well as on the inflammatory processes associated with a range of respiratory tract disorders. Nevertheless, there is debate as to whether the principal response to PAR activation is an augmentation or attenuation of airways inflammation. In this context, an important action of PAR activators may be to promote the generation and release of prostanoids, such as prostglandin E2, which have well-established anti-inflammatory effects in the lung. In this review, we primarily focus on the relationship between PARs, prostaglandins and inflammatory processes in the lung, and highlight their potential role in selected respiratory tract disorders, including pulmonary fibrosis, asthma and chronic obstructive pulmonary disease. This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009 [source] Molecular mechanisms underlying inflammatory lung diseases in the elderly: Development of a novel therapeutic strategy for acute lung injury and pulmonary fibrosis,GERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 3 2005Takahide Nagase In the elderly, inflammatory lung diseases, including acute lung injury and pulmonary fibrosis, are significant in terms of both mortality and difficulty in management. Acute respiratory distress syndrome (ARDS) is an acute lung injury and the mortality rate for ARDS ranges from 40 to 70% despite intensive care. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disorder of the lung parenchyma. No useful drugs are currently available to treat IPF. However, molecular mechanisms underlying these lung diseases are little understood and the development of a novel therapeutic strategy is urgently needed. Platelet-activating factor (PAF) and metabolites of arachidonic acid, i.e. eicosanoids, are lipid mediators that have various biological effects. A key enzyme for the production of these inflammatory mediators, including eicosanoids and PAF, is phospholipase A2. In particular, cytosolic PLA2 (cPLA2) is especially important. The purpose of this article is to report novel findings regarding the role of PAF and cPLA2 in lung inflammatory diseases, especially, acute lung injury and pulmonary fibrosis. To address this question, we used mutant mice, i.e. PAFR transgenic mice, PAFR gene-disrupted mice and cPLA2 gene-disrupted mice. We have shown that PAF and eicosanoids, downstream mediators of cPLA2, may be involved in the pathogenesis of ARDS and IPF, which are important diseases in the elderly. Although there exist extreme differences in clinical features between ARDS and IPF, both diseases are fatal disorders for which no useful drugs are currently available. On the basis of recent reports using mutant mice, cPLA2 might be a potential target to intervene in the development of pulmonary fibrosis and acute lung injury in the elderly. [source] The central role of Fas-ligand cell signaling in inflammatory lung diseasesJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2004G. A. DosReis Abstract Following inflammation and injury in the lung, loss of epithelial cell precursors could determine the balance between tissue regeneration and fibrosis. This review discusses evidence that proapoptotic Fas-Fas ligand (FasL) signaling plays a central role in pulmonary inflammation, injury and fibrosis. FasL signaling induces inflammatory apoptosis in epithelial cells and alveolar macrophages, with concomitant IL-1, and chemokine release, leading to neutrophil infiltration. FasL signaling plays a critical role in models of acute lung injury, idiopathic pulmonary fibrosis and silicosis; blockade of Fas-FasL interactions either prevents or attenuates pulmonary inflammation and fibrosis. Serologic and immunohistochemical studies in patients support a major pathogenic role of Fas and FasL molecules in inflammatory lung diseases. Identification of the pathogenic role of FasL could facilitate the discovery of more effective treatments for currently untreatable inflammatory lung diseases. [source] Alveolar and bronchial nitric oxide output in healthy childrenPEDIATRIC PULMONOLOGY, Issue 12 2008Anna Sepponen MD Abstract Exhaled nitric oxide (NO) concentration is a marker of pulmonary inflammation. It is usually measured at a single exhalation flow rate. However, measuring exhaled NO at multiple flow rates allows assessment of the flow-independent NO parameters: alveolar NO concentration, bronchial NO flux, bronchial wall NO concentration, and bronchial diffusing capacity of NO. Our aim was to determine the flow-independent NO parameters in healthy schoolchildren and to compare two different mathematical approaches. Exhaled NO was measured at four flow rates (10, 50, 100, and 200 ml/sec) in 253 schoolchildren (7,13 years old). Flow-independent NO parameters were calculated with linear method (flows ,50 ml/sec) and non-linear method (all flows). Sixty-six children (32 boys and 34 girls) with normal spirometry and no history or present symptoms of asthma, allergy, atopy or other diseases were included in the analysis. Median bronchial NO flux was 0.4 nl/sec (mean,±,SD: 0.5,±,0.3 nl/sec) and median alveolar NO concentration was 1.9 ppb (2.0,±,0.8 ppb) with the linear method. Bronchial NO flux correlated positively with height (r,=,0.423; P,<,0.001), FEV1 (r,=,0.358; P,=,0.003), and FVC (r,=,0.359; P,=,0.003). With the non-linear method, median bronchial wall NO concentration was 49.6 ppb (68.0,±,53.3 ppb) and bronchial diffusing capacity of NO was 10.0 pl/sec/ppb (11.8,±,7.5 pl/sec/ppb). The non-linear method gave lower alveolar NO concentration (1.4 [1.5,±,0.7] ppb, P,<,0.001) and higher bronchial NO flux (0.5 [0.6,±,0.3] nl/sec, P,<,0.001) than the linear method, but the results were highly correlated between the two methods (r,=,0.854 and r,=,0.971, P,<,0.001). In conclusion, the multiple flow rate method is feasible in children but different mathematical methods give slightly different results. Reference values in healthy children are of value when applying bronchial and alveolar NO parameters in the diagnostics and follow-up of inflammatory lung diseases. Pediatr. Pulmonol. 2008; 43:1242,1248. © 2008 Wiley-Liss, Inc. [source] Protease inhibitors derived from elafin and SLPI and engineered to have enhanced specificity towards neutrophil serine proteasesPROTEIN SCIENCE, Issue 3 2009Marie-Louise Zani Abstract The secretory leukocyte protease inhibitor (SLPI), elafin, and its biologically active precursor trappin-2 are endogeneous low-molecular weight inhibitors of the chelonianin family that control the enzymatic activity of neutrophil serine proteases (NSPs) like elastase, proteinase 3, and cathepsin G. These inhibitors may be of therapeutic value, since unregulated NSP activities are linked to inflammatory lung diseases. However SLPI inhibits elastase and cathepsin G but not proteinase 3, while elafin targets elastase and proteinase 3 but not cathepsin G. We have used two strategies to design polyvalent inhibitors of NSPs that target all three NSPs and may be used in the aerosol-based treatment of inflammatory lung diseases. First, we fused the elafin domain with the second inhibitory domain of SLPI to produce recombinant chimeras that had the inhibitory properties of both parent molecules. Second, we generated the trappin-2 variant, trappin-2 A62L, in which the P1 residue Ala is replaced by Leu, as in the corresponding position in SLPI domain 2. The chimera inhibitors and trappin-2 A62L are tight-binding inhibitors of all three NSPs with subnanomolar Kis, similar to those of the parent molecules for their respective target proteases. We have also shown that these molecules inhibit the neutrophil membrane-bound forms of all three NSPs. The trappin-2 A62L and elafin-SLPI chimeras, like wild-type elafin and trappin-2, can be covalently cross-linked to fibronectin or elastin by a tissue transglutaminase, while retaining their polypotent inhibition of NSPs. Therefore, the inhibitors described herein have the appropriate properties to be further evaluated as therapeutic anti-inflammatory agents. [source] Role of interleukin-17F in chronic inflammatory and allergic lung diseaseCLINICAL & EXPERIMENTAL ALLERGY, Issue 9 2006N. Hizawa Summary IL-17 family members belong to a distinct category of cytokines that coordinate local tissue inflammation by inducing the release of pro-inflammatory and neutrophil-mobilizing cytokines. The importance of the IL-17 family in inflammatory and autoimmune disease is becoming increasingly apparent. IL-17F is a recently discovered member of the IL-17 family that has a number of biological activities through induction of various cytokines, chemokines, and mediators. IL-17A, the founding member of the IL-17 family, and IL-17F are produced by several inflammatory cells, including activated T cells, in response to infectious and antigenic stimuli. Overexpression of IL-17A or IL-17F in the lungs results in induction of CXC chemokines and neutrophil recruitment. In a case,control study of 1125 unrelated Japanese subjects, a His161 to Arg161 (H161R) substitution in the third exon of the IL17F gene was shown to be associated with asthma and chronic obstructive pulmonary disease (COPD). Functionally, this variant failed to induce cytokines and chemokines, and interestingly, was able to antagonize the activity of wild-type IL-17F. These results provide an experimental basis for the observed genetic association with chronic inflammatory lung diseases, and also suggest the potential therapeutic utility of this antagonistic variant of IL-17F. Given that asthma and COPD are complex diseases involving a number of genetic and environmental factors, the genetic impact of IL-17F H161R with regard to the development of chronic airway inflammation likely varies among individuals with different genetic backgrounds and environmental exposures. [source] | ||||||||||