The phosphodiesterase type IV inhibitor cilomilast decreases pro-inflammatory cytokine production from primary bronchial epithelial cells in lung transplantation patients.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) remains the major cause of long-term morbidity and mortality after lung transplantation, and new therapeutic measures are needed. We speculated that cilomilast might reduce mediators of airway inflammation and angiogenesis from the airway epithelium, supporting a potential value in the treatment of BOS. We used an ex vivo primary bronchial epithelial cell culture (PBEC) model to investigate this hypothesis. Increasing evidence suggests the epithelium is central in stimulating both inflammatory and proliferative responses in the airway. METHODS: Bronchial brushings were taken from 7 stable lung allograft recipients and were used to establish sub-confluent PBECs. The effect of incubation for 48 hours with 0.1 to 10 micromol/liter cilomilast on basal production of interleukin (IL)-8, IL-6, granulocyte macrophage colony-stimulating factor (GMCSF), and vascular endothelial growth factor (VEGF) were assayed by multiplex analyser. RESULTS: There was a dose dependent fall in basal IL-8 and GMCSF levels with cilomilast. Median change for IL-8 was -25% (range, -66% to 5%; p = 0.035) at 1 micromol/liter , and -40% (range, -72% to -20; p = 0.022) at 10 micromol/liter. Median GMSCF change was -34% (range, -70% to 16%; p = 0.05) at 1 micromol/liter, and 37% (range, -80% to -8%; p = 0.04) at 10 micromol/liter. There were no effects on VEGF. CONCLUSION: The phosphodiesterase type IV inhibitor cilomilast reduced IL-8 and GMCSF release from PBECs. These cytokines are associated with the persistence of airway neutrophilic inflammation and airway remodelling seen in obliterative bronchiolitis. These ex vivo results suggest a potential for cilomilast in the treatment of BOS, which would need to be evaluated in appropriate clinical studies.

A descriptive study of small airway reticular basement membrane thickening in clinically stable lung transplant recipients.

BACKGROUND: Chronic rejection functionally manifested by fixed airflow limitation, bronchiolitis obliterans syndrome (BOS), is a major problem for all lung allograft programs. The inclusion of a pre-BOS category (BOS(0 approximately p)) in the newly revised guidelines, recognizes the potential importance of early changes. We tested the hypothesis that small airway reticular basement membrane thickening exists even in clinically stable lung transplant recipients with some evidence of inflammation but who are BOS-free. METHODS: A bronchoscopic study was performed on 30 clinically stable lung allograft recipients at >/=3 months post-allograft, who were BOS-free but with some evidence of airway inflammation indicated by a pathologic diagnosis of lymphocytic bronchiolitis or raised exhaled nitric oxide (NO). After baseline physiologic assessment, small airway reticular basement membrane (Rbm) thickening was quantified in transbronchial biopsy (TBB) using image analysis, with inflammation assessed by bronchoalveolar lavage (BAL) differential cell counts. RESULTS: Twenty-one patients had technically satisfactory measurements of Rbm thickness. We detected small airway Rbm thickening when compared with published data for control lung diseases. There was no correlation between Rbm thickening and lung function (forced expiratory volume in 1 second [FEV(1)] best post-operatively and Rbm r = -0.10, not significant). CONCLUSIONS: Our data suggest that airway remodeling can occur early in lung allografts and before development of airflow limitation and BOS. Longitudinal pathophysiologic studies are needed to elucidate potential relationships between airway inflammation, Rbm thickening and allograft failure. Airway biopsies would be of value in such studies.