Gene Expression Profiling in Murine Obliterative Airway Disease

Abstract

Lung and heart-lung transplantation are effective treatments for many diseases unresponsive to other therapy. However, long-term survival of recipients is limited by the development of obliterative bronchiolitis (OB). In this study, microarray analysis of a heterotopic mouse model of obliterative airway disease (OAD) was used to test the hypothesis that the expression and patterns of genes will correlate with specific changes in tracheal tissue developing a response to allotransplantation and the infiltrating cells manifesting these changes. Expression profiles observed were in accordance with the current paradigm of a predictable sequence of events, beginning with airway injury; an innate immune response followed by an adaptive immune response, including both cell-mediated and humoral components; and eventual loss of airway epithelial cells. These observations confirm and expand the list of genes and molecular processes that can be studied as potential surrogate markers or targets for intervention of OB.

Searching for novel molecular targets of chronic rejection in an orthotopic experimental lung transplantation model

“…We found that changes in gene expression originated directly from the transplanted lung that showed histologic signs of CR at 90 days, as described in rats, 16,17 and could be compared with other microarray studies. [8][9][10] In this model of inbred rats, we detected native expression of genes originally involved in CR, which has not been observed in previous studies, where immunosuppressants modulated the response to rejection.…”

“…In our study, Tgfb was the second most prominent up-regulated pathway and Tgfb1 mRNA was significantly increased, suggesting that this pathway has a major role in the pathogenesis of AR and CR, but has not been described in previous microarray studies. 8,9 These findings could have clinical relevance since it has been reported that Tgfb expression is increased in patients with BOS, even prior to the onset of airflow obstruction, 10 and Tgfb is able to directly induce pulmonary fibrosis. 24 The main activities of Tgfb1 are cell growth inhibition and induction of apoptosis.…”

“…2,6 There is a need for a better understanding of the underlying molecular mechanisms in the pathogenesis of BOS. Toward this end, DNA microarray technology allows us to rapidly explore genomic functions in obliterative airway disease 8 and bronchoalveolar lavage of LT recipients, 9,10 but, currently, there are no reports of BOS in orthotopic LT using this technology. Potential findings could improve our understanding of the physiopathology of BOS, would establish a foundation for identifying molecular targets, and may contribute to the development of specific therapeutic strategies for improving the life expectancy of LT patients.…”

Longitudinal protein expression patterns in bronchiolitis obliterans syndrome

“…Thymosin beta-4 enhances the survival of transplanted mesenchymal stem cells for cardiac repairby reducing apoptosis [17]. In addition, gene expression profiling from a murine model of obliterative bronchiolitis demonstrated an increase in thymosin expression [18]. These studies suggest that thymosin may promote cellular and tissue growth in the development of BOS.…”

MDQC: a new quality assessment method for microarrays based on quality control reports

“…Although there is an open debate on whether the measures contained in the QC reports can identify quality problems, QC reports are commonly used to assess the quality of microarrays (Finkelstein, 2005;Landea et al, 2005). One common practice is to compare the values of each measure against ad hoc thresholds.…”