In vivo levels and in vitro production of interferon-gamma in fibrosing interstitial lung diseases

Abstract

SUMMARY The in vivo role of interferons in the development of fibrosis is not fully understood but it is known that interferons can suppress fibroblast proliferation and collagen synthesis in vitro. We have recently demonstrated that in a group of patients with sarcoidosis having predominant pulmonary involvement, patients with the highest levels of circulating interferon‐gamma (IFN‐y) more frequently resolved on corticosteroids, suggesting that they had a less‘fibrotic’ component to their disease. We now report that in two other diseases, where the tendency to develop pulmonary fibrosis is greater than in sarcoidosis, namely cryptogenic fibrosing alveolitis (CFA) and fibrosing alveolitis associated with the systemic connective tissue disease progressive systemic sclerosis (FA + PSS), very few patients have elevations in IFN‐γ in their serum. However, as in sarcoidosis, those with the highest levels responded to corticosteroids (P < 0·05). Attempts to measure IFN‐γ levels in the lungs, using cell‐free bronchoalveolar lavage (BAL) fluid supernatants, were negative in all the study groups, suggesting that these samples may be inadequate for such studies. To investigate whether there might be an intrinsic defect in T lymphocyte function associated with predisposition to fibrosing lung diseases, we then investigated the in vitro production of IFN‐y by lymphocytes separated from the blood of 18 untreated patients (six with CFA, six with FA + PSS and six with sarcoidosis). IFN‐γ production was impaired in 10 (56%) (two with CFA, four with FA + PSS and four with sarcoidosis). A higher proportion of the fibrosing alveolitis patients (CFA or FA + PSS) with impaired IFN‐γ production have subsequently shown spontaneous lung functional deterioration. These findings suggest that impaired IFN‐γ release might be a potentiating factor in the pathogenesis of these fibrosing lung diseases.

Effect of recombinant human IFNγ in the treatment of chronic pulmonary complications due to sulfur mustard intoxication

“…Previous findings have indicated that IFNg inhibits fibroblast proliferation in pulmonary tissue, thereby reducing extracellular matrix and connective tissue formation (Li & Zhai, 2008). These findings have been corroborated by observations on the complete or partial deficiency of IFNg in patients with pulmonary fibrosis compared to normal subjects (Gurujeyalakshmi & Giri, 1995;Prior & Haslam, 1992). Besides, IFNg can counterbalance T H 2-associated cytokine overproduction and down-regulate gene expression of TGFb-one of the most potent fibrogenic factors (Du Bois, 1999;Ziesche & Block, 2000).…”

“…Several lines of evidence have shown that T H 2 cytokines and fibroblast count are elevated in patients with pulmonary fibrosis, which enhance TGFb status and accumulation of collagen in the airways (Raghu et al, 1989;Rahman, 2005). There is also evidence indicating impaired IFNg production in patients with fibrosing lung diseases (Prior & Haslam, 1992) that results in the over-proliferation of fibroblasts and excessive collagen production.…”

Review: New perspectives in the treatment of idiopathic pulmonary fibrosis

“…[2007] study, IPF lymphocytes showed higher than normal production of IL-4 but not of IFN-γ . Although this data need to be considered with caution since the diagnosis of CFA might include subjects with NSIP in addition to IPF/UIP patients, it is worth noticing that in Prior and Haslam's [1992] study, higher IFN-γ levels were associated with better response to corticosteroid treatment and better prognosis in CFA-affected individuals.…”

“…In a "cryptogenetic fibrosing alveolitis" (CFA) (a synonym of IPF) study, Prior and Haslam [1992] found that most diseased subjects had low levels of circulating IFN-γ . Wallace and Co-workers showed that most lymphocytes infiltrating the interstitium in CFA expressed IL-4 and IL-5 but almost none IFN-γ [Wallace et al 1995]; type II alveolar epithelial cells expressed IL-4, but no IFN-γ at sites of disease, while they expressed both IL-4 and IFN-γ in allergic alveolitis [Wallace and Howie 1999], suggesting that the TH2 type response may be important in the pathogenesis of lung fibrosis.…”

“…Antifibrotic agents Interferon-γ Based upon the observation of a general impairment of the production of interferon-γ patients with fibrosing alveolitis [Prior and Haslam, 1992], Ziesche et al [1996] carried out a non-randomized open-label trial using interferon-γ in IPF. The same group did subsequently carry out a second open label clinically controlled trial on 18 IPF patients: this trial demonstrated a significant improvement in lung function and arterial oxygenation following therapy with interferon-γ 1b 200 mcg three times per week s.c., and low dose prednisolone, when compared to prednisolone alone [Ziesche et al 1999].…”