Matthias C. Kugler, MD

Two areas of interest evolved from my research and clinical activities. On the cell biology level, I am interested in how cell surface receptors communicate with their environment in physiologic and pathophysiologic states. The functional consequences of altered signaling are of particular interest for me as a physician since they give me further insight into disease mechanisms, such as aberrant integrin or growth factor receptor signaling in pulmonary fibrosis. On the clinical level, I have become particularly interested in IPF (idiopathic pulmonary fibrosis), a fatal, progressive lung disease with unpredictable clinical course, a median survival of <4 years and no effective treatment. Despite extensive research its underlying mechanisms remain unclear. One potential way I have studied involves EMT. In EMT, epithelial cell injury induces phenotype change to a mesenchymal type, resulting in interstitial matrix accumulation in alveolar walls and progressive pulmonary fibrosis with loss of function. Another potential mechanism I am currently studying involves embryonic signaling pathways, such as Hedgehog (HH) signaling, which are usually suppressed in adult uninjured lung, but might become reactivated as pathogenic mechanism in IPF.

In our lab we have shown HH pathway reactivation in lung fibroblasts in two important settings: (1) during alveolar septum formation in the postnatal lung and (2) in bleomycin-injured fibrotic lung. In the early postnatal developmental setting, inhibition of HH signaling produced alveolar airspace enlargement and septum wall thinning without affecting septum formation. This indicates the importance of precise temporal decrease in mesenchyme for normal lung structure. In the pathophysiological setting, the exacerbation of bleomycin-induced fibrosis by SHH over-expression implies that aberrant pathway activity prevents the demise of lung fibroblasts during fibrosis resolution.

The long-term goals of my work are to better understand the molecular signatures of pulmonary fibrosis by studying their characteristics in pathophysiologically relevant mouse models to elucidate novel mechanisms and improve treatment options.