Insulin-like growth factor-1 (IGF-1) is a highly mitogenic polypeptide detectable in human lung. Using competitive reverse transcriptase/polymerase chain reaction (RT-PCR), expression of four IGF-1 transcripts was examined in bronchoalveolar lavage cells (BALC) from normal subjects, idiopathic pulmonary fibrosis (IPF), stage I/II (no fibrosis), and stage III/IV (confirmed fibrosis) pulmonary sarcoidosis patients, and fibroblast strains isolated from normal and IPF lungs. Transcripts studied were Class 1 and Class 2 (exons 1 or 2, respectively) with IGF-1Eb or IGF-1Ea (exons 5 or 6, respectively). Total IGF-1 expression was downregulated in BALC of both patients with IPF (p < 0.01) and patients with sarcoidosis (p < 0.04) compared with healthy subjects. In contrast, both constitutive (p < 0.003) and transforming growth factor-beta (TGF-beta)- induced (p < 0.02) IGF-1 expression was higher in fibrotic, compared with normal, fibroblasts. These changes were associated with differential expression of IGF-1 splice variants. Healthy subjects and sarcoidosis patients without fibrosis showed similar expression of Class 1/Class 2 and IGF-1Ea/IGF-1Eb. However, patients with fibrosis demonstrated discordant, increased relative abundance of Class 1 transcripts (p < 0.01). In parallel, all fibrosis patients failed to express Class 2, IGF-1Eb forms and sarcoidosis patients with fibrosis did not express the Class 1, IGF-1Eb variant either. Fibrotic fibroblasts expressed higher constitutive levels of Class 1, IGF-1Ea transcripts compared with normal fibroblasts. Class 2, IGF-1Eb forms were moderately expressed by fibroblasts only after stimulation with TGF-beta, which also further increased levels of Class 1, IGF-1Ea transcripts. Our findings suggest that transition from a healthy to a fibrotic phenotype occurs in association with a changing pattern of IGF-1 mRNA heterogeneity and leads us to hypothesize a potential role for specific IGF-1 variants in fibrogenesis.

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A 67-yr-old female was admitted with a two week history of dry cough, cold sores and progressive breathlessness. Her exercise tolerance had gradually reduced over 3 yrs from 3 miles to half a mile. Three years previously she was diagnosed as having chronic myeloid leukaemia for which she received a total of 1.3 g busulphan, producing remission for the last 2 yrs. She was an exsmoker with a 40 pack-yr history. There was no relevant occupational history. The only regular medication was allopurinol.On examination she was breathless at rest, cyanosed but afebrile, pulse rate 110 beats . min -1 , respiratory rate 24 beats . min -1 , blood pressure 120/70, normal jugular venous pressure and heart sounds. On examination of the chest, percussion notes were normal and auscultation revealed bilateral basal crackles. The remainder of the examination was normal.Full blood count showed normocytic normochromic anaemia with haemoglobin (Hb) 88 g . L -1 and leukocytosis with white blood cell (WBC) count 17.2610 9 cells . L -1 , erythrocyte sedimentation rate (ESR) was raised to 80 (normal 0±20) and C-reative protein (CRP) was raised to 164 mg . L -1 (normal range 0±9). The chest radiograph on admission is shown in figure 1. Autoimmune profile, blood culture, sputum culture, urine culture, viral serology and protein electrophoresis were normal. Arterial blood gas analysis on air showed arterial oxygen tension (Pa,O 2 ) 3.5 kPa and arterial carbon dioxide tension (Pa,CO 2 ) 3.3 kPa, the Pa,O 2 increasing to 11.7 kPa on 50% oxygen. Dynamic spirometry showed a restrictive ventilatory defect forced expiratory volume in one second (FEV1) 0.95 (61% pred), forced vital capacity (FVC) 0.97 (51% pred), FEV1/FVC ratio 98%. Shunt fraction determined by breathing 100% oxygen was grossly elevated at 40%.High-resolution computed tomography (HRCT) was performed ( fig. 2). Fibreoptic bronchoscopy showed normal endobronchial anatomy. Owing to severe hypoxia, bronchoalveolar lavage (BAL) was not performed. Fluid obtained from bronchial washing was colourless and was negativeforPneumocystiscariniipneumonia(PCP).Transbronchial biopsy concluded at the same time confirmed the diagnosis ( fig. 3).

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