Early Changes in Basement Membrane Thickness in Airway Walls Post-Lung Transplantation Lucas Law, BSc(Hons), a Ling Zheng, MD, PhD, a Bernadette Orsida, BSc, a Bronwyn Levvey, BEdSt., RN, b Takahiro Oto, MD, b A. Thomas C. Kotsimbos, MD, a,b Gregory I. Snell, MBBS, a,b and Trevor J. Williams, MBBS a,b Background: Identification of early histopathologic markers of future bronchiolitis obliterans syndrome (BOS) may enable preemptive targeted intervention, delaying and perhaps preventing the onset of BOS. This study aimed to determine if early changes in airway epithelial basement membrane thickness predisposes transplant recipients to the subsequent development of BOS. Methods: Basement membrane thickness was measured in serial endobronchial biopsies taken from 29 initially stable lung transplant recipients (sLTR) recruited 148  80 days post-transplant and followed for 3 years. A further 2 years of clinical follow-up was undertaken without biopsies to follow lung function and define ultimate BOS status. Nine healthy subjects (non-atopic, non- asthmatic) were recruited as controls. Sections of paraffinized endobronchial biopsies were stained for collagen type I immunohistochemically, and basement membrane thickness was assessed by computer image analysis. Results: BOS developed in 21 of 29 patients in the 5 years of follow-up, 16 of which had endobronchial biopsies available for analysis before BOS developed (ever-BOS). The first endobronchial biopsies showed increased BMT in the combined sLTR and ever-BOS patients compared with the controls. This initial increase in basement membrane thickness resolved to normal levels within 300 days post-transplant, with a strong negative correlation (r 2 = 0.424, p  0.0001) of basement membrane thickness vs time. Paradoxically, the sLTR tended to have the greatest basement membrane thickness at baseline. Conclusion: An initial increase in basement membrane thickness is seen in the airway walls of all lung transplant recipients. This is transient and does not appear to be a risk factor for the subsequent development of BOS in lung allograft recipients. J Heart Lung Transplant 2005;24:1571–76. Copyright © 2005 by the International Society for Heart and Lung Transplantation. Bronchiolitis obliterans syndrome (BOS) is the most common cause of death in recipients beyond 1 year post-lung transplantation. 1,2 Pathologically, BOS is caused by a fibroproliferative lesion of small airways that leads to dysfunction and obliteration. The charac- teristic histologic lesion is that of obliterative bronchi- olitis. 3,4 Transbronchial biopsy lacks sensitivity in detect- ing obliterative bronchiolitis, and repeated thoracoscopic or open lung biopsies are not practical. Studies 5,6 have confirmed the utility of endobronchial biopsies in eval- uating patients with BOS, showing that larger airways have a pattern of cellular infiltration, cytokine up- regulation, and when more severe grades of BOS (Grades 2– 4) are present, an increased deposition of Type III collagen that in turn leads to increased base- ment membrane thickness (BMT). 7 Normally, collagen provides both mechanical and phys- iologic support to local cells as an extracellular matrix network with its production tightly regulated by growth factors and cytokines. 8 It is known that corticosteroids inhibit collagen production, 9,10 whereas metalloprotein- ases (tissue inhibitor of metalloproteinases [TIMPS]) de- grade it. 11 Among cytokines, transforming growth factor- (TGF-), a pleiotropic growth factor, can either potently stimulate or inhibit collagen synthesis, depending largely on the local concentration of its active form. 11,12 Indeed, elevated levels of interleukin-8 and TGF- in bronchoal- veolar lavage (BAL) from BOS patients have been reported previously, 13 leading to the suggestion that they may be important in mediating the fibroproliferative lesion. 14,15 Pathologic fibrosis occurs when deregulation of syn- thesis and/or degradation occurs, leading to the accu- From the a Department of Medicine, Monash University, and b Depart- ment of Allergy, Immunology and Respiratory Medicine, Alfred Hos- pital, Melbourne, Australia. Submitted October 31, 2004; revised January 7, 2005; accepted January 13, 2005. Supported by Novartis Pharmaceuticals, Margaret Pratt Heart-Lung Research Foundation, Bennalong Foundation, and Alfred Hospital Whole Time Medical Specialists Trust. Reprint requests: Associate Professor Trevor J. Williams, Depart- ment of Allergy, Immunology and Respiratory Medicine, Alfred Hos- pital, Melbourne 3004, Australia. Telephone: +61 3 9276 2489. Fax: +61 3 9276 3601. E-mail: Trevor.Williams@med.monash.edu.au Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2005.01.007 1571