BACKGROUND The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk. METHODS Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. MUC5B expression was assessed in lung tissue. RESULTS Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes. The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P = 1.2×10−15; allelic association with idiopathic pulmonary fibrosis, P = 2.5×10−37). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% confidence interval [CI], 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P<0.001). The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wild-type allele, P<0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis. CONCLUSIONS A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dys-regulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

We performed a genome-wide association study in non-Hispanic white subjects with fibrotic idiopathic interstitial pneumonias (N=1616) and controls (N=4683); replication was assessed in 876 cases and 1890 controls. We confirmed association with TERT and MUC5B on chromosomes 5p15 and 11p15, respectively, the chromosome 3q26 region near TERC, and identified 7 novel loci (PMeta = 2.4×10−8 to PMeta = 1.1×10−19). The novel loci include FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13), and chromosomal regions 7q22 and 15q14-15. Our results demonstrate that genes involved in host defense, cell-cell adhesion, and DNA repair contribute to the risk of fibrotic IIP.

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Patients with chronic obstructive pulmonary disease (COPD) often report anxiety, depression and poor health status, not least if they experience repeated hospitalisations due to acute exacerbations. The aim of this study was to analyse the interrelationships between health status, anxiety, depression and physical status in COPD patients being discharged after hospitalisation. This was a prospective study of 416 patients in five university hospitals in each of the Nordic countries. Data included demographic information, lung function and co-morbidity. The Hospital Anxiety and Depression Scale and St. George's Respiratory Questionnaire (SGRQ) were applied to all patients. Both anxiety and depression were common among these patients. Anxiety was more common in women than in men (47% vs. 34%, P=0.009) and current smokers had a higher prevalence of both anxiety (54% vs. 37%) and depression (43% vs. 23%) than non-smokers (P<0.01). In general, the studied COPD patients had poor health status, especially those with anxiety, depression or both. Psychological status was independently related to all dimensions of SGRQ. Higher GOLD stages were significantly associated with increasing impairment in health status. In conclusion this multicentre study showed that anxiety and depression are common in patients with COPD, and, furthermore, that patients with psychological disorders have poor health status. Screening for depression and anxiety may help to identify patients with poor quality of life and an urgent need for intervention in order to improve their health status.

Farmers lung disease is a common form of hypersensitivity pneumonitis (HP) and is characterized by inflammation and granuloma formation in the lung. Interferon-␥ is important for the expression of granulomatous diseases caused by infectious agents; however, the role this mediator in regulating expression of the granulomatous response to inhaled antigen is not known. To evaluate this, we compared the response to inhaled antigen of mice that do not express the gene coding for interferon-␥ (GKO) with that of their normal littermates (WT). GKO and WT mice on a BALB/c background were exposed to 150 g of the thermophilic bacteria Saccharopolyspora rectivirgula or saline alone, for three consecutive days a week, for 3 wk. After exposure to antigen, WT mice developed a marked granulomatous inflammation associated with an increase in lung weight and numbers of cells in bronchoalveolar lavage fluid (BAL). Although GKO mice also exhibited an increase in lung weight and numbers of cells in BAL fluid, they developed minimal inflammation and no granulomas after a similar exposure to antigen. To further evaluate if the lack of a response to antigen in GKO mice was due to lack of IFN -␥ , we replaced this mediator via intraperitoneal injections. When given replacement IFN-␥ , the GKO mice developed granulomatous inflammation in the lung. These studies show that IFN-␥ is essential for the expression of hypersensitivity pneumonitis. ( J. Clin. Invest. 1997. 99:2386-2390.)

The partnership-based self-management programme had benefits concerning perception of the intrusiveness of chronic obstructive pulmonary disease and its treatment on lifestyles, activities and interests for young patients with the disease in its early stages. High satisfaction in control group, low family attendance and the relatively short treatment period may explain the less than expected benefits of the programme.

Hypersensitivity pneumonitis (HP) is an inflammatory lung disease characterized by granuloma formation. We recently showed that interferon-gamma (IFN-gamma) is essential for inflammation and granuloma formation in HP. Interleukin-10 (IL-10) counteracts many of the biologic effects of IFN-gamma, suggesting that IL-10 modulates inflammation and granuloma formation in HP. We compared the expression of HP in C57BL/6 mice that lack IL-10 (IL-10 knockout [KO]) with that in wild-type (WT) littermates. IL-10 KO and WT mice were exposed to the thermophilic bacteria Saccharopolyspora rectivirgula or to saline alone for 3 wk. The IL-10 KO mice had higher cell counts in their bronchoalveolar lavage fluid (2.85 +/- 0. 43 x 10(6)) than did WT mice (1.4 +/- 0.3 x 10(6)/ml; P < 0.03), with a more prominent neutrophil response. They also had greater inflammation after antigen exposure than did the WT mice (P < 0. 0001). There was increased upregulation of IFN-gamma, IL-1, and tumor necrosis factor-alpha (TNF-alpha) mRNAs in the lungs of IL-10 KO mice. Adenovirus-mediated gene transfer of IL-10 to the liver of IL-10 KO mice reduced the inflammation from that seen in WT mice. These studies show that IL-10 has important anti-inflammatory properties in HP, and that lack of this cytokine leads to a more severe granulomatous inflammatory response.