leukotriene-e4 and Cystic-Fibrosis

We investigated the hypothesis that cysteinyl leukotriene (LT) production is altered in atopic patients with cystic fibrosis (CF).. Urinary LTE4 was measured in two groups of children with CF: atopic (ACF group, n = 22) and nonatopic (NACF group, n = 13); and in two groups of unaffected children, those with atopic asthma (AA group, n = 11) and nonatopic normal control subjects (NN group, n = 12).. Atopic groups excreted significantly more urinary LTE4 (geometric means [95% confidence intervals] in picomoles per millimole creatinine), ACF group: 104 (73-147) and AA group: 195 (136-282) compared with NACF group: 19 (9-39) and NN group: 27 (15-48). The ACF group had significantly more airflow obstruction than the NACF group, with forced expiratory volume in 1 second (percent predicted, mean +/- SD) in ACF: 58 +/- 21 versus NACF: 81 +/- 23, and forced vital capacity (percent predicted, mean +/- SD) 72 +/- 17 versus 87 +/- 23, respectively. There were significant correlations between the degree of airflow obstruction, bronchodilator responsiveness, and urinary LTE4 concentration within the entire CF group. We used multiple regression analysis to assess the respective influence of age, atopy, sensitization to Aspergillus fumigatus, and colonization with Pseudomonas aeruginosa on urinary LTE4 concentration. The atopic state was the only significant variable associated with urinary LTE4 production in subjects with CF.. The similarities in urinary LTE4 between ACF and AA groups suggest that the atopic state is the prime determinant of urinary LTE4 excretion. Enhanced cysteinyl LT production associated with atopy in CF may increase the severity of pulmonary disease.

Topics: Adolescent; Adult; Asthma; Child; Child, Preschool; Cystic Fibrosis; Female; Forced Expiratory Volume; Heterozygote; Homozygote; Humans; Hypersensitivity; Leukotriene E4; Lung; Male; Mutation; Osmolar Concentration; Pulmonary Ventilation; Reference Values

Sputum samples from 13 children with cystic fibrosis (CF) were analyzed for leukotrienes (LTs) LTB4, LTC4, LTD4, and LTE4. Distribution of LTB4 appeared to be normal, and of cysteinyl-LTs log normal. Total cysteinyl-LT levels, of which on average 75% was LTE4, were nearly 10 times higher than in earlier studies. Log LTE4 and total cysteinyl-LT levels correlated with the overall severity of pulmonary disease assessed by Chrispin-Norman chest radiograph score (Log LTE4: r = 0.701, r2 = 49.1%, P = 0.008. Log total cysteinyl-LTs: r = 0.715, r2 = 51.1%, P = 0.006). There was no apparent relationship between LTB4 levels and Chrispin-Norman chest radiograph score, nor between the level of any of the LTs and age or organism cultured from sputum. These findings suggest that the cysteinyl-LTs may be involved in the pathophysiology of pulmonary disease in CF.

Topics: Child; Chromatography, High Pressure Liquid; Cystic Fibrosis; Humans; Leukotriene E4; Leukotrienes; Lung; Radiography; Radioimmunoassay; Respiratory Tract Infections; Sputum; SRS-A

1. Leukotrienes (LTs) are potent pro-inflammatory mediators with actions relevant to the pathophysiology of cystic fibrosis (CF), including increased mucus production, bronchoconstriction, leucocyte chemotaxis, and increased vascular permeability. We have therefore investigated the potential role of LTs in children with CF. Leukotriene E4 levels were assessed in the urine of 30 normal (N) children (aged 1.3-12.7 years) and 30 CF children (1.6-14.3 years). Sputum from 13 of the CF children was analysed from LTB4, LTC4, LTD4, and LTE4. LTs were separated by reversed-phase h.p.l.c. and quantitated by radioimmunoassay. 2. Urinary LTE4 levels were log normally distributed, with geometric mean values (95% confidence intervals) of N: 88.4 (71.3-111) pmol mmol-1 creatinine (n = 30), and CF: 112 (70.6-177) pmol mmol-1 creatinine (n = 30; P greater than 0.05). Of the CF subjects, 33% had urinary LTE4 levels above 200 pmol mmol-1 creatinine, compared with 3.3% of the N children. 3. In sputum, mean (+/- s.e. mean) LT concentrations were (pmol g-1), LTB4: 44.3 +/- 10.8, LTC4: 4.9 +/- 1.3, LTD4: 1.8 +/- 0.9, and LTE4: 67.7 +/- 18.9 (n = 13). 4. Urinary LTE4 levels correlated significantly with sputum LTE4 levels (r = 0.673, P = 0.012), and with sputum levels of total cysteinyl-LTs (r = 0.660, P = 0.014). 5. In conclusion, total cysteinyl-LT content in sputum is 10-fold higher than previously reported, consisting primarily (91%) of LTE4. The high levels of LTE4 and LTB4 in sputum suggest involvement of LTs in the pathophysiology of CF. Urinary LTE4 levels may prove useful as a marker for cysteinyl-LT production in sputum.

Topics: Adolescent; Child; Child, Preschool; Chromatography, High Pressure Liquid; Cystic Fibrosis; Humans; Infant; Leukotriene B4; Leukotriene E4; Leukotrienes; Radioimmunoassay; Sensitivity and Specificity; Sputum; SRS-A

The recent definition of the pathways of generation and structures of diverse products of the lipoxygenation of arachidonic acid has established the identity of a new family of mediators of hypersensitivity and inflammation. Studies of the effects of these mediators have shown that leukotrienes C, D, and E, the constitutents of the slow-reacting substance of anaphylaxis (SRS-A), are extremely potent smooth muscle contractile and vasoactive factors. Leukotriene B is a highly active stimulus of neutrophil and eosinophil functions and suppresses the immunological capabilities of T lymphocytes. The development of specific and sensitive radioimmunoassays has permitted the detection of elevated concentrations of leukotrienes in tissues or exudates in several diseases, including asthma, diverse allergic states, adult respiratory distress syndrome, psoriasis, spondyloarthritis, and gout. The application of selective inhibitors and antagonists of leukotrienes will clarify their pathogenetic contributions in human diseases and may yield new therapeutic approaches.

Topics: Arachidonate Lipoxygenases; Arachidonic Acids; Arthritis; Asthma; Cystic Fibrosis; Humans; Hypersensitivity; Leukotriene A4; Leukotriene B4; Leukotriene E4; Lipoxygenase; Psoriasis; SRS-A; Tears