Publications

BACKGROUND

Clinical studies have shown that injurious mechanical ventilation is associated with increased airspace and plasma levels of interleukin-1beta (IL-1beta); however, the potential therapeutic value of IL-1 inhibition in acute lung injury has not been thoroughly investigated. A study was undertaken to determine if IL-1 signalling is a necessary early event in the pathogenesis of experimental ventilator-induced lung injury.

METHODS

Mice deficient in IL-1 receptor type 1 (IL1R1) and rats treated with IL-1 receptor antagonist (IL-1Ra) were mechanically ventilated with high tidal volume (30 ml/kg) and the effect of IL-1 signalling blockade on the severity of lung injury was determined.

RESULTS

Permeability, as measured by radiolabelled albumin flux, was significantly lower in IL1R1 null mice than in wild-type mice during injurious ventilation (p<0.05). IL-1Ra significantly decreased protein permeability and pulmonary oedema in rats during injurious ventilation and also decreased airspace and plasma levels of the chemokine CXCL1 and airspace neutrophils. IL-1Ra decreased expression of NOS2 and ICAM-1 mRNA in whole lung. Bronchoalveolar lavage fluid levels of RTI40, a marker of type I cell injury, were 2.5 times lower following IL-1Ra treatment (p<0.05). In isolated type II pneumocytes, IL-1beta reduced electrical resistance and increased transepithelial permeability.

CONCLUSIONS

IL-1 contributes to alveolar barrier dysfunction in VILI by promoting lung neutrophil recruitment and by increasing epithelial injury and permeability. Because preserved alveolar barrier function is associated with better outcomes in patients with acute lung injury, these data support further testing of IL-1Ra for the treatment of acute lung injury.

RATIONALE

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease lacking effective treatment.

OBJECTIVES

To determine the effects of bosentan on exercise capacity and time to disease progression in patients with IPF.

METHODS

In a double-blind, multicenter trial, patients with IPF were randomized to receive oral bosentan 62.5 mg twice daily for 4 weeks, increased to 125 mg twice daily thereafter, or placebo, for 12 months or longer. The primary efficacy endpoint was change from baseline up to Month 12 in exercise capacity, as measured by a modified six-minute-walk test. Secondary endpoints were time to death or disease progression (worsening pulmonary function tests [PFTs] or acute decompensation), change in PFT scores, and quality of life (QOL) assessed using Short-Form 36 and St. George's Respiratory Questionnaire.

MEASUREMENTS AND MAIN RESULTS

A total of 158 patients randomly received bosentan (n = 74) or placebo (n = 84). Bosentan showed no superiority over placebo in six-minute-walk distance (6MWD) up to Month 12, the primary efficacy endpoint. A trend in favor of bosentan was observed in the secondary endpoint of time to death or disease progression (hazard ratio [HR], 0.613; 95% confidence interval [CI], 0.328-1.144; P = 0.119), which was more pronounced in a patient subgroup diagnosed using surgical lung biopsy (post hoc analysis; HR, 0.315; 95% CI, 0.126-0.789; P = 0.009). Changes from baseline up to Month 12 in assessments of dyspnea and QOL favored treatment with bosentan. No unexpected adverse events were reported.

CONCLUSIONS

Bosentan treatment in patients with IPF did not show superiority over placebo on 6MWD. A trend in delayed time to death or disease progression, and improvement in QOL, was observed with bosentan. The more pronounced treatment effect in patients with biopsy-proven IPF warrants further investigation. Clinical trial registered with www.clinicaltrials.gov (NCT 00071461).

BACKGROUND & AIMS

Most previous population-based studies of mortality in inflammatory bowel disease (IBD) did not account for medication use. We evaluated mortality by IBD medication use among members of the Kaiser Permanente Northern California IBD Registry.

METHODS

The retrospective, population-based cohort study included 9032 persons who received at least one inpatient or 2 outpatient diagnoses of IBD during 1996-2002. Age and sex standardized mortality ratios measured the associations between IBD and all-cause and cause-specific mortality. Age, sex, and smoking adjusted odds ratios measured the association of mortality by IBD medication use.

RESULTS

Compared with health plan members without IBD, mortality was increased in patients with Crohn's disease (CD) (1.4; 95% confidence interval, 1.2-1.6) but not ulcerative colitis (UC) (1.0; 95% CI, 0.9-1.2). CD was associated with increased mortality from infectious and parasitic diseases (4.1; 95% CI, 1.7-8.5), septicemia (6.8; 95% CI, 2.2-15.8), small intestinal cancer (48.1; 95% CI, 5.8-17.4), respiratory diseases (1.9; 95% CI, 1.3-2.7), digestive diseases other than IBD (2.4; 95% CI, 1.0-4.8), and liver diseases (2.6; 95% CI, 1.0-5.3). UC was associated with increased mortality from digestive diseases other than IBD (3.9; 95% CI, 2.4-6.0). The relationship with CD mortality was 0.7 for aminosalicylates (95% CI, 0.5-1.1), 1.3 (95% CI, 0.9-1.9) for immunomodulators, and 1.0 (95% CI, 0.7-1.4) for corticosteroids. Among patients with UC, these odds ratios were 0.8 (95% CI, 0.5-1.1) for aminosalicylates, 0.5 (95% CI, 0.3-0.9) for immunomodulators, and 0.8 (95% CI, 0.6-1.1) for corticosteroids.

CONCLUSIONS

Mortality is increased in CD. Infections, respiratory diseases, and digestive diseases are important specific causes of death. IBD medication use has varying associations with mortality.

Airway inflammation and epithelial remodeling are two key features of asthma. IL-13 and other cytokines produced during T helper type 2 cell-driven allergic inflammation contribute to airway epithelial goblet cell metaplasia and may alter epithelial-mesenchymal signaling, leading to increased subepithelial fibrosis or hyperplasia of smooth muscle. The beneficial effects of corticosteroids in asthma could relate to their ability to directly or indirectly decrease epithelial cell activation by inflammatory cells and cytokines. To identify markers of epithelial cell dysfunction and the effects of corticosteroids on epithelial cells in asthma, we studied airway epithelial cells collected from asthmatic subjects enrolled in a randomized controlled trial of inhaled corticosteroids, from healthy subjects and from smokers (disease control). By using gene expression microarrays, we found that chloride channel, calcium-activated, family member 1 (CLCA1), periostin, and serine peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2) were up-regulated in asthma but not in smokers. Corticosteroid treatment down-regulated expression of these three genes and markedly up-regulated expression of FK506-binding protein 51 (FKBP51). Whereas high baseline expression of CLCA1, periostin, and serpinB2 was associated with a good clinical response to corticosteroids, high expression of FKBP51 was associated with a poor response. By using airway epithelial cells in culture, we found that IL-13 increased expression of CLCA1, periostin, and serpinB2, an effect that was suppressed by corticosteroids. Corticosteroids also induced expression of FKBP51. Taken together, our findings show that airway epithelial cells in asthma have a distinct activation profile and identify direct and cell-autonomous effects of corticosteroid treatment on airway epithelial cells that relate to treatment responses and can now be the focus of specific mechanistic studies.

BACKGROUND

One type of fecal occult blood test (FOBT), the unrehydrated guaiac fecal occult blood test (GT), is recommended by the United States Preventive Services Task Force and the Institute of Medicine for use in screening programs, but it has relatively low sensitivity as a single test for detecting advanced colonic neoplasms (cancer and adenomatous polyps > or = 1 cm in diameter). Thus, improving the sensitivity of FOBT should make colon cancer screening programs that use these tests more effective.

METHODS

We assessed prospectively the performance characteristics of two newer FOBTs in 5841 subjects at average risk for colorectal cancer in a large group-model managed care organization. The tests evaluated included a sensitive GT, a fecal immunochemical test (FIT), and the combination of both tests. Patients with positive and negative test results were advised to have colonoscopy and sigmoidoscopy, respectively. Sensitivity and specificity for detecting advanced neoplasms in the left colon within 2 years after the FOBT screening were evaluated for the two tests administered separately and in combination.

RESULTS

A total of 139 patients were diagnosed with advanced colorectal neoplasms (n = 14 cancers, n = 128 adenomas) within the 2 years following their initial FOBT screening. Sensitivity for detecting cancer was 81.8% (95% confidence interval [CI] = 47.8% to 96.8%) for the FIT alone and 64.3% (95% CI = 35.6% to 86.0%) for the sensitive GT and the combination test. Sensitivity for detecting advanced colorectal adenomas was 41.3% (95% CI = 32.7% to 50.4%) for the sensitive GT, 29.5% (95% CI = 21.4% to 38.9%) for the FIT, and 22.8% (95% CI =16.1% to 31.3%) for the combination test. Specificity for detecting cancer and adenomas was 98.1% (95% CI = 97.7% to 98.4%) and 98.4% (95% CI = 98.0% to 98.7%), respectively, for the combination test; 96.9% (95% CI = 96.4% to 97.4%) and 97.3% (95% CI = 96.8% to 97.7%), respectively, for the FIT; and 90.1% (95% CI = 89.3% to 90.8%) and 90.6% (95% CI = 89.8% to 91.4%), respectively, for the sensitive GT.

CONCLUSIONS

The FIT has high sensitivity and specificity for detecting left-sided colorectal cancer, and it may be a useful replacement for the GT.