ABSTRACT
Idiopathic pulmonary fibrosis [IFF] and chronic hypersensitivity pneumonitis [HP] are diffuse parenchyma! lung diseases characterized by a mixture of inflammation and fibrosis, leading to lung destruction and finally death. The aim of this study was to compare different pathophysiological mechanisms, such as angiogenesis, coagulation, fibrosis, tissue repair, inflammation, epithelial damage, oxidative stress, and matrix remodeling, in both disorders using bronchoalveolar lavage [BAL]. At diagnosis, patients underwent bronchoscopy with BAL and were divided into three groups: Control [n = 10], HP [n = 11], and IPF [n = 11], based on multidisciplinary approach [clinical examination, radiology, and histology]: Multiplex searchlight technology was used to analyze 25 proteins representative for different pathophysiological processes: Eotaxin, basic fibroblast growth factor [FGFb], fibronectin, hepatocyte growth factor [HGF], interleukine [IL]-8, IL-12p40, IL-17, IL-23, monocyte chemotactic protein [MCP-1], macrophage-derived chemokine [MDC], myeloperoxidase [MPO], matrix metalloproteinase [MMP]-8, MMP-9, active plasminogen activating inhibitor 1 [PAI-1], pulmonary activation regulated chemokine [PARC], placental growth factor [PIGF], protein-C, receptor for advanced glycation end products [RAGE], regulated on activation normal T cells expressed and secreted [RANTES], surfactant protein-C [SP-C], transforming growth factor-pi [TGF-]31], tissue inhibitor of metalloproteinase-1 [TIMP-1], tissue factor, thymic stromal lymphopoietin [TSLP], and vascular endothelial growth factor [VEGF]. All patients suffered from decreased pulmonary function and abnormal BAL cell differential compared with control. Protein levels were increased in both IPF and HP for MMP-8 [P = 0.022], MMP-9 [P- 0.0020], MCP-1 [P - 0.0006], MDC [P = 0.0048], IL-8 [P - 0.013] MPO [P - 0.019] and protein-C [P = 0.0087], whereas VEGF was decreased [P = 0.0003] compared with control. HGF was upregulated in HP [P = 0.0089] and active PAI-1 was upregulated [P = 0.019] in IPF compared with control. Differences in expression between IPF and HP were observed for IL-12p40 [P = 0.0093] and TGF-p1 [P= 0.0045]. Using BAL, we demonstrated not only expected similarities but also important differences in both disorders, many related to the innate immunity. These findings provide new clues for further research in both disorders
ABSTRACT
Increase in size and number of bronchial blood vessels as well as hyperaemia are factors that contribute to airway wall remodelling in patients with chronic airway diseases, such as asthma and chronic obstructive pulmonary diseases (COPD). Expression of transforming growth factor 1 (TGF-1), a multifunctional cytokine as well as vascular endothelial growth factor (VEGF), a key angiogenic molecule, has been shown in the inflammed airways in patients with chronic airway diseases. TGF-1 has been implicated in the regulation of extracellular matrix, leading to airway remodelling in patients with chronic airway diseases. However, the role of TGF-1 in regulating VEGF expression in patients with chronic airway diseases, as well as the underlying mechanisms are not yet well established. We investigated whether TGF-1 stimulates VEGF expression in vitro and hence could influence vascular remodelling. Cultured human airway smooth muscle cells (HASMC) were serum deprived for 60 h before incubation with 5ng/ml of TGF-1 for different time points. Control cells received serum-free culture medium. TGF‑1, treatment resulted in time dependent HASMC cell proliferation with maximal values for DNA biosynthesis at 24 h and cell number at 48 h. Northern blot analysis of VEGF mRNA expression showed increased levels in cells treated with TGF-1 for 4 to 8 h. TGF-1 also induced a time-dependent release of VEGF proteins in the conditioned medium after 48 h of treatment. Furthermore, the ability of HASMC-released VEGF proteins to induce human umbilical vein endothelial cells proliferation was inhibited by VEGF receptor antagonist, confirming that TGF-1 induced VEGF was biologically active. We conclude that TGF-1 in addition to an extracellular matrix regulator also could play a key role in bronchial angiogenesis and vascular remodelling via VEGF pathway in asthma.