Lymphangiogenic factors are associated with the severity of hypersensitivity pneumonitis

Abstract

BackgroundAntigen presenting cells play a pivotal role in the adaptive immune response in hypersensitivity pneumonitis (HP). It was hypothesised that lymphangiogenesis is involved in the pathophysiology of HP via cell transport.ObjectiveTo determine the clinical significance of lymphangiogenic factors in HP.MethodsLevels of vascular endothelial growth factors (VEGF)-A, VEGF-C, VEGF-D and CCL21 in the serum and bronchoalveolar lavage fluid (BALF) were measured in 29 healthy volunteers, 14 patients with idiopathic pulmonary fibrosis (IPF) and 26 patients with HP by ELISA. Additionally, immunohistochemical analyses were performed using lung specimens of patients with HP (n=8) and IPF (n=10).ResultsBALF VEGF-D levels were significantly elevated in patients with HP compared to the other groups. BALF VEGF–D levels in patients with HP correlated significantly with the BALF total cell and lymphocyte counts (r=0.485, p=0.014 and r=0.717, p<0.0001, respectively). BALF VEGF-C and CCL21 levels were increased in patients with HP compared to healthy volunteers, but not patients with IPF. BALF CCL21 levels were negatively correlated with the forced expiratory volume in 1 s percentage and diffuse capacity of the lung for carbon monoxide (r=−0.662, p=0.007 and r=−0.671, p=0.024, respectively). According to the immunohistochemical analyses, CCL21 was expressed in the lymphatic endothelium in both conditions and CCR7+ cells were aggregated around lymphatics in patients with HP, but not in patients with IPF.ConclusionsLymphangiogenic factors might be associated with the inflammatory and functional severity of HP. The increased BALF VEGF-D levels were associated with lymphatic alveolitis intensity, and CCL21 with lung function impairment.

VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease

“…In the small cohorts examined thus far, analogous to ARDS and IPF, BALF VEGF-A levels are reduced in patients with HP [ 115 , 117 ]. In contrast, serum VEGF-A levels appear increased compared to controls [ 117 , 118 ] and IPF patients [ 118 ].…”

“…In a small cohort of acute and subacute HP patients, BALF VEGF-C and VEGF-D levels were elevated compared to healthy controls, with increased levels of VEGF-D but not VEGF-C compared to IPF patients. Furthermore, VEGF-D levels correlated with HP inflammatory severity as determined by BALF lymphocytosis [ 118 ]. Further work is required to explore this apparent association.…”

Assessment of pulmonary 18 F-FDG-PET uptake and cytokine profiles in non-small cell lung cancer patients treated with radiotherapy and erlotinib

“…CCL21 has not previously been associated with therapy response in the normal lung, neither following RT nor erlotinib therapy. Patients with hypersensitivity pneumonitis showed an increase in CCL21 levels and bronchoalveolar lavage fluid compared to healthy volunteers [40] . Moreover, studies have shown that CCL21 is increased in patients with inflammatory skin disease [41] , [42] , and erlotinib therapy is associated with skin rash and release of inflammatory cytokines [43] .…”

Low lymphatic vessel density associates with chronic rhinosinusitis with nasal polyps

“…Similarly, in a murine mycoplasma pulmonis driven model of chronic airway inflammation, lymphatic sprouting was completely inhibited by a long course of antibiotics, but lymphatic vessels regressed only partly in comparison to the almost complete regression of blood vessels (34). In humans, lymphangiogenesis has been documented to increase in idiopathic pulmonary fibrosis (41) .…”