Linking Microscopic Spatial Patterns of Tissue Destruction in Emphysema to Macroscopic Decline in Stiffness Using a 3D Computational Model

Pulmonary emphysema is a connective tissue disease characterized by the progressive destruction of alveolar walls leading to airspace enlargement and decreased elastic recoil of the lung. However, the relationship between microscopic tissue structure and decline in stiffness of the lung is not well understood. In this study, we developed a 3D computational model of lung tissue in which a pre-strained cuboidal block of tissue was represented by a tessellation of space filling polyhedra, with each polyhedral unit-cell representing an alveolus. Destruction of alveolar walls was mimicked by eliminating faces that separate two polyhedral either randomly or in a spatially correlated manner, in which the highest force bearing walls were removed at each step. Simulations were carried out to establish a link between the geometries that emerged and the rate of decline in bulk modulus of the tissue block. The spatially correlated process set up by the force-based destruction lead to a significantly faster rate of decline in bulk modulus accompanied by highly heterogeneous structures than the random destruction pattern. Using the Karhunen-Loève transformation, an estimator of the change in bulk modulus from the first four moments of airspace cell volumes was setup. Simulations were then obtained for tissue destruction with different idealized alveolar geometry, levels of pre-strain, linear and nonlinear elasticity assumptions for alveolar walls and also mixed destruction patterns where both random and force-based destruction occurs simultaneously. In all these cases, the change in bulk modulus from cell volumes was accurately estimated. We conclude that microscopic structural changes in emphysema and the associated decline in tissue stiffness are linked by the spatial pattern of the destruction process

Alveolar Dynamics and Beyond – The Importance of Surfactant Protein C and Cholesterol in Lung Homeostasis and Fibrosis

Surfactant protein C (SP-C) is an important player in enhancing the interfacial adsorption of lung surfactant lipid films to the alveolar air-liquid interface. Doing so, surface tension drops down enough to stabilize alveoli and the lung, reducing the work of breathing. In addition, it has been shown that SP-C counteracts the deleterious effect of high amounts of cholesterol in the surfactant lipid films. On its side, cholesterol is a wellknown modulator of the biophysical properties of biological membranes and it has been proven that it activates the inflammasome pathways in the lung. Even though the molecular mechanism is not known, there are evidences suggesting that these two molecules may interplay with each other in order to keep the proper function of the lung. This review focuses in the role of SP-C and cholesterol in the development of lung fibrosis and the potential pathways in which impairment of both molecules leads to aberrant lung repair, and therefore impaired alveolar dynamics. From molecular to cellular mechanisms to evidences in animal models and human diseases. The evidences revised here highlight a potential SP-C/cholesterol axis as target for the treatment of lung fibrosis

Mesenchymal stem cells enhance survival and bacterial clearance in murine <em>Escherichia coli</em> pneumonia

RATIONALE: Bacterial pneumonia is the most common infectious cause of death worldwide and treatment is increasingly hampered by antibiotic resistance. Mesenchymal stem cells (MSCs) have been demonstrated to provide protection against acute inflammatory lung injury; however, their potential therapeutic role in the setting of bacterial pneumonia has not been well studied. OBJECTIVE: This study focused on testing the therapeutic and mechanistic effects of MSCs in a mouse model of Gram-negative pneumonia. METHODS AND RESULTS: Syngeneic MSCs from wild-type mice were isolated and administered via the intratracheal route to mice 4 h after the mice were infected with Escherichia coli. 3T3 fibroblasts and phosphate-buffered saline (PBS) were used as controls for all in vivo experiments. Survival, lung injury, bacterial counts and indices of inflammation were measured in each treatment group. Treatment with wild-type MSCs improved 48 h survival (MSC, 55%; 3T3, 8%; PBS, 0%; p<0.05 for MSC vs 3T3 and PBS groups) and lung injury compared with control mice. In addition, wild-type MSCs enhanced bacterial clearance from the alveolar space as early as 4 h after administration, an effect that was not observed with the other treatment groups. The antibacterial effect with MSCs was due, in part, to their upregulation of the antibacterial protein lipocalin 2. CONCLUSIONS: Treatment with MSCs enhanced survival and bacterial clearance in a mouse model of Gram-negative pneumonia. The bacterial clearance effect was due, in part, to the upregulation of lipocalin 2 production by MSCs