Dr. Steven Shapiro’s Research
Dr. Shapiro’s laboratory focuses on the role of inflammatory cell derived proteinases in the progression of COPD/emphysema and lung cancer. He originally cloned and knocked-out macrophage elastase (MMP-12) to demonstrate that MMP-12 deficient mice are completely protected from the development of cigarette smoke-induced emphysema. Dr. Shapiro’s lab has continued to study the contribution of numerous inflammatory cell derived proteinases in emphysema and lung cancer progression using gene targeting in mice. More recently, his lab has begun to study the role of repair (or lack thereof) in the progression of emphysema by using lineage-tagging approaches to study putative stem cell populations residing within the lung.
Inflammatory-Cell Interactions in Chronic Obstructive Pulmonary Disease (COPD) and the Role of Histone Acetylation.
Reactive oxygen species resulting from inhaled cigarette smoke (and potentially from the inflammatory cells themselves) promote transcription of nuclear factor-κB (NF-κB)–mediated proinflammatory factors by way of two mechanisms. First, oxidation results in the degradation of IK-κB, releasing NF-κB, which then translocates to the nucleus of the targeted cell. Oxidation also inactivates histone deacetylase (HDAC), shifting the balance to increased DNA acetylation, weakening the interactions between histone and DNA and “unwinding” DNA, allowing NF-κB greater access to the DNA promoter elements, and leading to transcription of neutrophil chemokines and cytokines (tumor necrosis factor TNF-1α and interleukin-8) and matrix metalloproteinases (MMPs). These factors recruit and activate neutrophils to the lung. In addition, CD8+ T cells augment the production of macrophage MMPs through interactions with surface-bound CD40 molecules and interferon-inducible chemokines (inducible protein of 10 kD [IP-10], interferon-inducible T-cell alpha chemoattractant [I-TAC], and monokine induced by interferon-γ[MIG]). Macrophage MMPs and neutrophil elastase degrade each other’s inhibitors, the tissue inhibitor of metalloproteinases and alpha1-antitrypsin, respectively, augmenting their matrix-degrading capacities. These interactions illustrate the highly interactive nature of the immune inflammatory response and suggest that breaking this cycle, perhaps by way of augmentation of HDAC with the use of theophylline, may prevent inflammatory-mediated destruction of the lung in COPD. Dashed lines indicate inhibition.
Hypothesized common origins of emphysema and lung cancer.
Under normal conditions, lung homeostasis is preserved via low-level cell turnover with alveolar macrophages patrolling the lower airspace to remove invading pathogens and particles. Upon exposure to cigarette smoke, inflammatory cells, particularly neutrophils and macrophages, are recruited and activated causing them to release serine and matrix metalloproteinases (MMPs) and reactive oxygen species (ROS). Emphysema results when extracellular matrix destruction and cell death exceeds reparative capacity leading to airspace enlargement. BASCs attempt to replace damaged alveolar cells and maintain alveolar integrity. However, repeated induction of BASC proliferation in the context of cigarette carcinogens and inflammatory proteinase-mediated release of growth factors predisposes these cells to become malignant, leading to bronchogenic carcinoma. Houghton et al., Nature Med 14, 1023-1024 (2008).
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