Natural production and functional effects of alternatively spliced interleukin-4 protein in asthma.

We have previously described an alternatively spliced isoform of IL-4 mRNA that omits exon 2 and is termed IL-4δ2. However, the natural production of IL-4δ2 protein and its association with disease have not been previously assessed due to unavailability of an antibody that interacts with IL-4δ2 without cross-reactivity with full length IL-4. We used a unique monoclonal antibody (mAb) that reacts with IL-4δ2, but not with IL-4, and observed that IL-4δ2 is naturally produced by T cells from patients with asthma, but not from healthy controls. The kinetics of IL-4δ2 and IL-4 production by phorbol myristate acetate (PMA)/ionomycin-activated cells differed, with IL-4δ2 increasing at 48-72h and IL-4 peaking at 24h. The steady-state levels of IL-4δ2 mRNA varied significantly among the donors and were discordant with the corresponding protein levels, suggesting post-transcriptional regulation of protein production. Polarized Th1 or Th2 lymphocytes were not a major source of IL-4δ2. Stimulation of cultured T lymphocytes with IL-4δ2 caused elevated production of IFN-γ, IL-10, IL-6, MCP-1, and TNF-α, with notable differences between patients and controls in the production of IFN-γ, IL-10, and IL-6. Thus, IL-4δ2 is natively produced not only as mRNA but also as a protein by cells other than Th1 or Th2. It is regulated post-transcriptionally, is associated with allergic asthma, and regulates production of other cytokines by primary T lymphocytes. Alternatively spliced interleukin-4 may be a new biomarker, a pathophysiological player, and possibly a molecular target for future therapies in asthma.

Centrilobular emphysema combined with pulmonary fibrosis results in improved survival.

BACKGROUND: We hypothesized that, in patients with pulmonary fibrosis combined with emphysema, clinical characteristics and outcomes may differ from patients with pulmonary fibrosis without emphysema. We identified 102 patients who met established criteria for pulmonary fibrosis. The amount of emphysema (numerical score) and type of emphysema (centrilobular, paraseptal, or mixed) were characterized in each patient. Clinical characteristics, pulmonary function tests and patient survival were analysed. RESULTS: Based on the numerical emphysema score, patients were classified into those having no emphysema (n = 48), trivial emphysema (n = 26) or advanced emphysema (n = 28). Patients with advanced emphysema had a significantly higher amount of smoking in pack/years than patients with no emphysema or trivial emphysema (P < 0.0001). Median survival [1st, 3rd quartiles] of patients with advanced emphysema was 63 [36, 82] months compared to 29 [18, 49] months in patients without emphysema and 32 [19, 48] months in patients with trivial emphysema (P < 0.001). Median forced vital capacity (FVC) and total lung capacity (TLC) were higher in the advanced emphysema group compared to patients with no emphysema (P < 0.01 and P < 0.001, respectively), whereas median DLCO did not differ among groups and was overall low. Within the advanced emphysema group (n = 28), further characterization of the type of emphysema was performed and, within these subgroups of patients, survival was 75 [58, 85] months for patients with centrilobular emphysema, 75 [48, 85] months for patients with mixed centrilobular/paraseptal emphysema, and 24 [22, 35] months for patients with paraseptal emphysema (P < 0.01). Patients with advanced paraseptal emphysema had similar survival times to patients without emphysema. CONCLUSIONS: Patients with pulmonary fibrosis combined with advanced centrilobular or mixed emphysema have an improved survival compared with patients with pulmonary fibrosis without emphysema, with trivial emphysema or with advanced paraseptal emphysema.

Variable prevalence of pulmonary hypertension in patients with advanced interstitial pneumonia.

BACKGROUND: Pulmonary hypertension may occur in patients with interstitial pneumonia and is associated with increased mortality. We sought to determine the prevalence of pulmonary hypertension in sub-groups of patients with interstitial pneumonia and to investigate possible associations between pulmonary vascular hemodynamics and pulmonary function. METHODS: The presence or absence of pulmonary hypertension was assessed in 70 patients with advanced interstitial pneumonia who underwent right heart catheterization. The associations of pulmonary hypertension with clinical characteristics and pulmonary function tests were analyzed. RESULTS: The prevalence of pulmonary hypertension in patients with idiopathic interstitial pneumonia was 29% vs 64% in patients with connective tissue disease-interstitial pneumonia (p = 0.013). African American patients had a significantly higher prevalence of pulmonary hypertension in the entire study population (81% vs 22%, p < 0.001) and in the idiopathic interstitial pneumonia group (70% vs 19%, p < 0.01). Regression analyses revealed no association between mean pulmonary artery pressure (mPAP) and forced vital capacity or mPAP and diffusion capacity of the lung for carbon monoxide in the entire cohort or in sub-groups of patients. CONCLUSIONS: African American patients and patients with connective tissue disease-interstitial pneumonia had a high prevalence of pulmonary hypertension. Non-African American patients with advanced idiopathic interstitial pneumonia (including idiopathic pulmonary fibrosis) had a low prevalence of pulmonary hypertension.