PURPOSE: The examination of HRCT scan images has revealed that around 20% of patients with IPF, primarily smoker males, exhibit the combination of pulmonary fibrosis and emphysematous lesions (CPFE). These patients display severe impaired carbon monoxide diffusing capacity, high prevalence of pulmonary arterial hypertension and higher mortality compared with those with IPF without emphysema. However, the pathogenic mechanisms implicated in the combination of both types of lung destruction (emphysema and fibrosis) are unknown. In this study we evaluated whether the expression of several MMPs, cytokines and chemokines may distinguish CPFE from IPF.
METHODS: We analyzed the levels of interleukin (IL)-1β, IL-5, IL-8, PDGF, TNF-α, TGF-α, TGF-β, endothelin-1, MMP-1, MMP-2, MMP-3, MMP- 7, MMP-9, MMP-12 and MMP-13, in the bronchoalveolar lavage (BAL) from 10 patients with CPFE, 7 with IPF, and 10 normal volunteers by multiplex. MMP-2 and -9 were examined by gelatin zymography. Lung localization of MMP-9 was analyzed by immunohistochemistry.
RESULTS: Our results showed a significant increase of MMP-9 in the patients with CPFE (5180.7±1741 vs. 2662.5±718 pg/mL in IPF, p<0.01). No MMP-9 was detected in controls. By gelatin zymography BAL supernatants of CPFE patients also exhibited a significant increase in pro-MMP-9 and MMP-9 gelatinolytic bands. By Immunohistochemistry strong staining was revealed in both IPF and CPFE tissues. MMP-9 was primarily localized in alveolar epithelial cells and neutrophils in CPFE and in epithelial cells and fibroblast foci in IPF. Also increased levels of TGF-β were found in CPFE (203.4±74.6 vs. 116±30.8 pg/mL in IPF, p<0.05). Four out of 10 CPFE patients exhibited detectable TGF-α. By contrast, IL-8 was significantly increased in IPF BAL fluids (2085.1±1016 vs. 582.7±470.5 in CPFE vs. 148.1± 67.4 pg/mL in controls; p<0.01).
CONCLUSIONS: These findings indicate that higher expression of lung MMP-9 and TGF-β and lower levels of IL-8 distinguish CPFE from IPF alone and suggest that they may play a role in the pathogenesis of combined pulmonary fibrosis with emphysema.
CLINICAL IMPLICATIONS: Our findings suggest that MMP-9 and TGF-β contributes to the development of CPFE, a more aggressive clinical phenotype in the patients with IPF.
DISCLOSURE: The following authors have nothing to disclose: Annie Pardo, Adrian Munguia, Remedios Ramirez, Jorge Garcia-Alvarez, Moises Selman
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