The lung provides a barrier that enables the exchange of oxygen and carbon dioxide between the atmosphere and bloodstream. The part of the barrier which faces the atmosphere (airspace) is covered by epithelial cells with different characteristics, depending upon the location in the lung. The terminal airspace (alveolus), where gas exchange occurs is covered by a layer of cells collectively known as the alveolar epithelium.
The alveolar epithelium is heterogeneous monolayer consisting of at least two cell types, type II cells and type I cells, which are in direct contact. Type I cells make up over 90% of the alveolar epithelial surface area, which is consistent with their role as the site of gas exchange between the atmosphere and capillary blood. However, there are roughly twice as many type II cells as there are type I cells. Assuming that both cell types are uniformly distributed throughout the alveolar epithelium, this suggests that nearly all type I cells are likely to be in direct contact with at least one type II cell, as well as with other type I cells.
At these cell-cell contacts there are a number of distinct elements which contribute to the function of alveolar epithelium. These include gap junctions and tight junctions. Gap junctions consist of channels composed of proteins in the connexin family. Gap junction channels enable the direct diffusion of molecules from one cell to it's nearest neighbor. these molecules include metabolites (ATP), antioxidants (glutathione), signaling molecules (cAMP, inositol trisphosphate) and ions (calcium). In other words, gap junctions enable cells in a tissue to be metabolically coupled to act as an integrated system.
Tight junctions are the primary mechanism that regulates whether the epithelium is tight or leaky. This is due to proteins in the claudin-family that form a seal to both restrict paracellular diffusion and permit specific transport of ions between cells across the epithelial barrier. There are nearly twenty different claudins, and cells simultaneously express several claudins. However, the mechanisms that regulate claudin intermixing are poorly understood at present. Also, it is not know how cells use multiple claudins to regulate epithelial barrier function. A primary goal of my laboratory is to use molecular and cell biological approaches to define roles for different claudins in normal lung barrier function and in pathologic conditions such as acute respiratory distress syndrome (ARDS). A long term goal is to develop methods to augment alveolar barrier function as a means to improve the outcome of patients with ARDS and other forms of lung injury.
Type II cells and type I cells express different connexins and claudins - suggesting that type I-type I cell interfaces are distinct from type I-type II cell interfaces. We are interested in determining how these different cells interact and defining roles for connexins and claudins in alveolar epithelial function.
Projects include:
Defining roles for gap junctional communication between type I and type II cells to regulate surfactant secretion.
Defining roles for gap junctional communication in the propagation and prevention of acute lung injury.
creating a pool of antioxidants shared between cells.
propagation of toxic substances during injury.
regulation of gap junctional communication to preserve type II cells.
Defining changes in claudin expression in response to acute lung injury and chronic alcohol abuse.
Determine whether tight junctions and and alveolar salt transport are coordinately regulated.
Selected References
Mitchell, L. A., C. E. Overgaard, C. Ward, S. S. Margulies and M. Koval. 2011. Differential effects of claudin-3 and claudin-4 on alveolar epithelial barrier function, Amer. J. Physiol. Lung Cell. Mol. Biol., 301:L40-49 (PubMed)
Koval, M., M. Billaud, A. C. Straub, A. Zarbock, B. R. Duling, B. E. Isakson, 2011. Spontaneous lung dysfunction and fibrosis in mice lacking connexin40 and endothelial cell connexin43, Amer. J. Path., 178:2536-2546. PMCID: PMC3124229..(PubMed)
Overgaard, C.E., B. L.Daugherty, L.A. Mitchell, M. Koval. 2011. Claudins: Control of Barrier Function and Regulation in Response to Oxidant Stress. Antioxid Redox Signal. 15:1179-93 (PubMed)
Koval, M., C. Ward, M.K. Findley, S. Roser-Page, M. N. Helms, J. Roman. 2010. Extracellular matrix influences alveolar epithelial claudin expression and barrier function, Amer. J. Respir. Cell Mol. Biol., 175:1799-1801. (PubMed)
Lassiter, C., X. Fan, P. C. Joshi, B. A. Jacob, R. L. Sutliff, D. P. Jones, M. Koval and D. M. Guidot. 2009. HIV-1 transgene expression in rats causes oxidant stress and alveolar epithelial barrier dysfunction. AIDS Research and Therapy, 6:1. PMCID: PMC2644707 (PubMed)
Johnson, L. N. and M. Koval. 2009. Crosstalk between injury-stimulated signaling, oxidant stress and pulmonary gap junctional communication. Antioxid. Redox. Signal., 11:355-367. (PubMed)
Daugherty, B.L., C. Ward, T. Smith, J. D. Ritzenthaler, M. Koval. 2007. Regulation of heterotypic claudin compatibility, J. Biol. Chem. 282:30005-30013. (PubMed)
Fernandez, A. L., M. Koval, X. Fan and D. M. Guidot. 2007. Chronic alcohol ingestion alters claudin expression in the alveolar epithelium of rats, Alcohol, 41:371-379. (PubMed)
Koval M. 2006. Connexins, tissue expression. in Encyclopedia of Respiratory Medicine, G. J. Laurent and S. D. Shapiro, editors. Elsevier, San Diego, CA., 558-560.
Fries D.M., R. Lightfoot, M. Koval and H. Ischiropoulos. 2005. Autologous Apoptotic Cell Engulfment Stimulates Chemokine Secretion by Vascular Smooth Muscle Cells. Am. J. Pathol. 167:345-353. (PubMed).
Patel A.S., D. Reigada, C. H. Mitchell, S. R. Bates, S. S. Margulies and M. Koval. 2005. Paracrine stimulation of surfactant secretion by extracellular ATP in response to mechanical deformation. Am J Physiol Lung Cell Mol Physiol. 289:L489-496. (PubMed).
Koval, M. and J. Bhattacharya. 2005. Vascular Gap Junctions. in Encyclopedia of the Microvasculature, David Shepro, editor. Elsevier, San Diego, CA.
Boitano, S., Z. Safdar, D.G. Welsh,J. Bhattacharya and M. Koval. 2004. EB meeting report: Cell-cell interactions between lung cells. Amer. J. Physiol. Lung Cell and Mol. Biol., 287:L455-9. (PubMed)
Daugherty, B., M. Mateescu, A. S. Patel, K. Wade, S. Kimura, L. W. Gonzales, P. L. Ballard and M. Koval. 2004. Developmental regulation of claudin localization by fetal alveolar epithelial cells, Amer. J. Physiol. Lung Cell. Mol. Biol., 287:L1266-1273. (PubMed).
Lin, G.C., J.K. Rurangirwa, M. Koval, and T.H. Steinberg. 2004. Gap junctional communication modulates agonist-induced calcium oscillations in transfected HeLa cells. J Cell Sci. 117:881-7.(PubMed).
Wang, F., B. Daugherty, L. L. Keise, Z. Wei, J. P. Foley, R. C. Savani, and M. Koval. 2003. Heterogeneous claudin expression by alveolar epithelial cells. 2003. Amer. J. Respir. Cell Mol. Biol., 29:62-70. DOI 10.1165/rcmb.2002-0180OC(PubMed)
Koval, M. 2002. Sharing signals: connecting lung epithelial cells with gap junctions. Amer. J. Physiol. Lung Cell and Mol. Biol. 283:L875-93.(PubMed)
Das Sarma, J., R. I. Meyer, F. Wang, V. Abraham, C. W. Lo and M. Koval. 2001. Multimeric connexin interactions prior to the trans Golgi apparatus. J. Cell Sci., 114:4013-4024. (PubMed)
Abraham, V., M. L. Chou, P. George, P. Pooler, A. Zaman, R. C. Savani and M. Koval. 2001. Heterocellular communication between alveolar epithelial cells. Amer. J. Phys. Lung Cell and Mol. Biol., 280:L1085-L1093.
(PubMed)
Abraham, V., M. Chou, K. DeBolt and M. Koval 1999. Phenotypic control of gap junctional communication by alveolar epithelial cells. Amer. J. Phys. Lung Cell and Mol. Biol. 276:L825-834.
(PubMed)
Lecanda, F., D. A. Towler, K. Ziambaras, S.-L. Cheng, M. Koval, T. H. Steinberg & R, Civitelli. 1998. Gap junctional communication modulates gene expression in osteoblastic cells. Mol. Biol. Cell, 9:2249-2258.
(PubMed)
Parry, G., E. Y.-H. Lee, D. Farson, M. Koval, and M. J. Bissell. 1985. Collagenous substrata regulate the nature and distribution of glycosaminoglycans produced by differentiated cultures of mouse mammary epithelial cells. Exp. Cell Res. 156:487-499.
(PubMed)
The lung provides a barrier that enables the exchange of oxygen and carbon dioxide between the atmosphere and bloodstream. The part of the barrier which faces the atmosphere (airspace) is covered by epithelial cells with different characteristics, depending upon the location in the lung. The terminal airspace (alveolus), where gas exchange occurs is covered by a layer of cells collectively known as the alveolar epithelium.
The alveolar epithelium is heterogeneous monolayer consisting of at least two cell types, type II cells and type I cells, which are in direct contact. 
Type I cells make up over 90% of the alveolar epithelial surface area, which is consistent with their role as the site of gas exchange between the atmosphere and capillary blood. However, there are roughly twice as many type II cells as there are type I cells. Assuming that both cell types are uniformly distributed throughout the alveolar epithelium, this suggests that nearly all type I cells are likely to be in direct contact with at least one type II cell, as well as with other type I cells.