University of Pennsylvania / School of Medicine / Beers Lab
The Beers' Laboratory for Surfactant Biology in the Pulmonary and
Critical Care Division in the Department of Medicine is housed in
state of the art wet bench space at the Translational Research
Center of the School of Medicine at 3400 Civic Center Boulevard.
Opened in December 2011, TRC combines world class research,
teaching, and animal care facilities, and is ideally positioned
contiguously with the Perelman Center for Advanced Medicine at the
Hospital of the University of Pennsylvania and adjacent to the
Children's Hospital of Philadelphia. This environment allows us to
leverage the very best of both institutions in order to facilitate
collaborative investigations in basic and translational biomedical
Research Portfolio of the Surfactant Biology Laboratories
The pulmonary epithelium synthesizes and secretes a surface-active film of biochemically heterogeneous lipoprotein mixture (lung surfactant) that reduces surface tension at air-liquid interfaces and allows for maintenance of alveolar stability at low lung volumes. [Figure 1] In addition two collagen-like lectin (“collectin”) protein components in surfactant are recognized for their importance in innate lung host defense and modulation of inflammation. Congenital and acquired abnormalities in surfactant component expression, in surfactant biophysics, and in the alveolar epithelial cells that produce it play an important role in the pathogenesis of adult and pediatric lung disease.
Our group is dedicated to the characterization of cellular and molecular mechanisms underlying surfactant biology and to an improved understanding of the role of the distal lung epithelium in the pathogenesis of lung disease. Current projects are focused on:
Biosynthetic Pathways for Surfactant Protein C (SP-C)
: Published work over the past 20 years by our group and others [Illustrated in Figure 2]
has defined the biosynthetic pathway for SP-C including demonstration of the importance of proper proprotein folding for correct trafficking and post-translational processing of the SP-C primary translation product (proSP-C). Current studies of pro-SP-C biosynthesis focus on the role of the regulation of its intracellular trafficking through its interactions with chaperones and other proteins and on the characterization of proteases/subcellular compartments involved in proteolytic processing.
- SP-C Mutations and Interstitial Lung Disease- We have shown that alterations in the proSP-C sequence that result in either misfolding or mistargeting of SP-C induce ER retention or formation of intracellular aggregates. Coincident with these observations, interstitial lung disease (ILD) in association with over 30 different heterozygous mutations in the SFTPC gene has been described, many of these with a structural homology with a protein associated with familial Alzheimer-like dementia (termed BRICHOS) [Figure 3].
From studies of other neurodegenerative diseases associated with mutations in proteins such as huntingin1, a-synuclein, and presenilin as well as in chronic liver disease associated with mutant a-1 antitrypsin, the concept of ‘conformational diseases’ caused by aggregation prone mutant proteins is well-recognized. We are currently characterizing mechanisms by which “SFTPC BRICHOS mutations” induce cell dysfunction [Figure 4] including formation of protein aggregates, generation of inflammation, and induction of apoptosis [See Movie]. Exciting new studies examining the novel role for macroautophagy in the lung for clearance of these aggregates and epithelial cytoprotection are also in progress and offer new therapeutic targets for pulmonary fibrosis. [Figure 5]
Biosynthesis and Function of ABCA3 in Health and Disease
: The ATP-binding cassette transporter ABCA3 is a member of the ABC superfamily of transporters that function in the translocation of substrates across cell membranes. Predominantly localized in the limiting membrane of the lamellar bodies of lung alveolar type II cells, ABCA3 is believed to function as a lipid and phospholipid transporter. Recently, ABCA3 has received considerable attention because mutations in the gene are associated with various lung disorders including fatal surfactant deficiency and respiratory distress syndrome (RDS) in newborns and interstitial lung disease (ILD) in older children and adults. Our studies are focused both on the functional aspects of ABCA3 as a transporter and on the cellular responses and consequences in cellular and pulmonary homeostasis as a result of expressing mutant isoforms of ABCA3. The overall objective of this project is to use a reductionist approach aimed at understanding the molecular mechanisms underlying ABCA3 biosynthesis, and to elucidate the consequences of expression of mutant isoforms of ABCA3 proteins associated with RDS and ILD. For more information please see Surafel Mulugeta, PhD
Epithelial Cell Dysfunction in the Pathogenesis of Parenchymal Disease-
Idiopathic interstitial pneumonia (IIP) represents a family of parenchymal lung diseases of unknown etiology characterized by progressive fibrotic remodeling. Recently, the concepts of epithelial cell dysfunction and abnormal wound healing have been implicated in the pathophysiology of IIP)
. In addition to SP-C and ABCA3 mutations, monogenetic diseases that specifically induce dysfunction of lung epithelial cells have been associated with the development of pulmonary fibrosis. On such disease is Hermansky-Pudlak Syndrome
(HPS). In collaboration with Dr. Susan Guttentag
at Children’s hospital Philadelphia, this project looks at mechanistic link(s) between the gene defects of HPS and chronic inflammation/fibrosis in the lung. We use mouse models of HPS for in vitro studies of alveolar type 2 cells and macrophages and for in vivo studies to determine the effects of interrupting the initiation phase versus the amplification phase of this process on the development of HPS lung disease.
The Role of Post-translational Modification of Pulmonary Collectins (Surfactant proteins A and D in Modulation of Lung Inflammation and Their Utility as Biomarkers [Figure 6]-
The lung is continuously exposed to inhaled pathogens (toxic pollutants, microorganisms, environmental antigens, allergens). The pulmonary immune system protects against harmful pathogens as a first line of defense and controls an inappropriate inflammatory response to harmless particles. In the bronchoalveolar space this critical balance is maintained by innate immune proteins, namely surfactant proteins. The primary function of the pulmonary collectins appears to be the modulation of host defense and inflammation. During the inflammatory state, despite normal pool sizes, the pulmonary collectins are inactivated, nitrated, oxidized, cross-linked or S-nitrosylated due to inflammatory mediators, cytokines, nitric oxide and other chemical mediators released by inflammatory cells. Some of the chemical modifications of collectins lead to alteration of its structure. Several studies suggest that multimerization of SP-A and SP-D is important for efficient influenza A virus neutralization and opsonization, binding Pneumocystis carinii and inhibition LPS-induced inflammatory cell responses. Our group demonstrated that during inflammation SP-D can become a direct target for post translational modification by NO. S-nitrosylation of SP-D result in breakdown of multimeric SP-D structure and exposing S-nitrosylated tail domain. In addition to loss of biological activity of the altered multimeric state of SP-D, the formation of SNO-SP-D trimers initiates a pro-inflammatory response. Thus, these findings support the concept that chemical modification of SP-D by NO results in alteration of its structure and therefore mediates its functions as both inflammatory inhibitor and activator.