Cystic fibrosis neutrophils

Graff I, Schram-Doumont A, Szpirer C. Defective protein kinase C-mediated actions in cystic fibrosis neutrophils. Cell Signal (1991) 259-66. 

PA S1 S01.131 Neutrophil elastase Drug target for emphysema, cystic fibrosis, adult respiratory distress syndrome, rheumatoid arthritis and other diseases... 

Damage to connective caused by leakage of elastases leads to damage associated with inflammatory diseases, such as pulmonary emphysema, adult respiratory distress syndrome, septic shock, cystic fibrosis, carcinogenesis, chronic bronchitis, and rheumatoid arthritis. Compounds that directly inhibit elastase or its release from human neutrophils are of enormous pharmaceutical and cosmetological interest in the development of new anti-inflammatory drugs. A possible source for elastase inhibitors are the medicinal Asteraceae and Droseraceae, particularly those used as traditional medicine in Asia. 

Human neutrophil elastase (HNE) is a serine containing enzyme which is one of the most destructive of proteolytic enzymes, being able to catalyze the hydrolysis of the components of connective tissue. It has been implicated in the development of diseases such as emphysema, cystic fibrosis, and rheumatoid arthrisis. /3-Sultams are excellent candidates for exploring the mechanism of sulfonation and possible inhibition of serine protease enzymes. A-Benzoyl... 

Cystic fibrosis is an autosomal recessive disease caused by mutations of the cystic fibrosis transmerobrane conductance regulator (CFTR) gene producing a dysfunctional chloride channel, normally located on the apical membrane of exocrine glands [16]. The disease manifests itself at an early age in the lung with accumulation of thick, sticky mucus and bacterial infections. These infections are followed by an inflammatory response, resulting in an Infiltration of neutrophils... 

ABPA is regarded as a complication of asthma, and occurs in approximately 1% of asthmatic patients. In addition to fever and malaise, the acute phase presents as an acute, easily reversible asthmatic syndrome with dyspnea and transient pulmonary infiltrations of eosinophils, neutrophils and lymphocytes, which may be effectively treated with corticosteroids. This condition usually progresses to a corticosteroid dependent and more intractable asthmatic state with transient pulmonary infiltrates (pulmonary eosinophilia) and a high sensitization to Aspergillus. From there the usual progression of the disease is to fibrosis and bronchiectasis. Most patients come to medical attention before the age of 35 years. The disease is a common complication of cystic fibrosis. 

Dornase alfa is phosphorylated glycosylated recombinant human deoxyribonuclease. It is given daily by inhalation of a nebulised solution containing 2500 units (2.5 mg). It is of modest value only in patients with cystic fibrosis, whose genetic defect in chloride transport causes particularly viscous sputum. The blocked airways, as well as the sputum itself, are a trap for pathogens and the lysis of invading neutrophils leads to substantial levels of free and very viscous DNA within the CF airways. 

Meyer KC, Zimmerman J. Neutrophil mediators. Pseudomonas, and pulmonary dysfunction in cystic fibrosis. J Lab Clin Med 121 (1993) 654-61. 

Meyer KC, Lewandoski JR, Zimmerman JJ, Nunley D, Calhoun WJ, Dopico GA Human neutrophil elastase and elastase/alpha 1-antiprotease complex in cystic fibrosis. Am J Respir Dis 144 (1991) 580-5. 

Meyer KC, Kewandeski JR, Zimmerman JJ, et al. Human neutrophil elas-tase and elastase/alphai -antiprotease complex in cystic fibrosis. Am Rev RespirESs 1991 144 580-585. 

Due to its broad specificity and high concentrations within neutrophils. NE has been implicated in the development and progression of several lung diseases such as pulmonary emphysema, cystic fibrosis, adult respiratory distress syndrome, and chronic bronchitis [2-4]. During phagocytosis and neutrophil turnover, there is a release of elastase into the extracellular environment which, if not controlled, can result in extensive damage to connective tissue. The destructive effect of elastase is normally controlled by endogenous proteinase inhibitors... 

Domase alfa is a mncolytic agent that cleaves DNA released by neutrophils that are mobilized to respiratory tract in response to infection, redncing viscoelasticity of pnrnlent Inng secretions, increasing airflow, and decreasing risk of infection. It is nsed in the treatment of cystic fibrosis. 

A study group to examine novel actions of macrolides was established in 1994 in Japan. Many clinicians and basic investigators have performed studies in many biological fields related to chronic inflammation. Some of these studies have been considered in this paper. Macrolides are likely to be useful for not only DPB but also other chronic neutrophil-induced inflammation, such as cystic fibrosis [88], These effects were associated with both modulation of host defense mechanisms and modulation of bacterial activity. New derivatives of erythromycin that showed... 

Two major but conflicting hypotheses have been proposed to explain the connection between abnormal CFTR activity in cystic fibrosis and the chronic neutrophil-dominated pulmonary inflammation and colonization with common bacteria. These hypotheses have been referred to as the high-salt hypothesis proposed by Michael Welsh and his colleagues at the University of Iowa, and the reduced pericellular volume hypothesis proposed by Richard Boucher and colleagues at the University of North Carolina. 

Figure 4 Neutrophil and IL-8 levels are increased in the BAL fluid of infants with cystic fihrosis. Elevations in neutrophils and IL-8 as seen in infants who were culture negative for common cystic fibrosis pathogens at the time of lavage. However, the levels of neutrophils and IL-8 were further increased in infants for whom organisms or viruses were detected in the BAL fluid. (From Ref. 70.)...

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