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Remodeling of the Aged and Emphysematous Lungs: Roles of Microenvironmental Cues

Béla Suki, Jason H.T. Bates, Erzsébet Bartolák‐Suki

10.1002/cphy.c210033

Source: Volume 12, Issue 3, July 2022

Published online: June 2022

Full Article on Wiley Online Library



Abstract

Aging is a slow process that affects all organs, and the lung is no exception. At the alveolar level, aging increases the airspace size with thicker and stiffer septal walls and straighter and thickened collagen and elastic fibers. This creates a microenvironment that interferes with the ability of cells in the parenchyma to maintain normal homeostasis and respond to injury. These changes also make the lung more susceptible to disease such as emphysema. Emphysema is characterized by slow but progressive remodeling of the deep alveolar regions that leads to airspace enlargement and increased but disorganized elastin and collagen deposition. This remodeling has been attributed to ongoing inflammation that involves inflammatory cells and the cytokines they produce. Cellular senescence, another consequence of aging, weakens the ability of cells to properly respond to injury, something that also occurs in emphysema. These factors conspire to make alveolar walls more prone to mechanical failure, which can set emphysema in motion by driving inflammation through immune stimulation by protein fragments. Both aging and emphysema are influenced by microenvironmental conditions such as local inflammation, chemical makeup, tissue stiffness, and mechanical stresses. Although aging and emphysema are not equivalent, they have the potential to influence each other in synergistic ways; aging sets up the conditions for emphysema to develop, while emphysema may accelerate cellular senescence and thus aging itself. This article focuses on the similarities and differences between the remodeled microenvironment of the aging and emphysematous lung, with special emphasis on the alveolar septal wall. © 2022 American Physiological Society. Compr Physiol 12:3559‐3574, 2022.

Figure 1. Figure 1. This figure illustrates the alveolar structure in human lungs from (A) a normal 29‐year‐old subject, (B) a 100‐year‐old subject without emphysema, (C) a patient with mild emphysema, and (D) a patient with severe emphysema. The red arrow on panel C indicates a site of rupture. (A, B) Reused, with permission, from Janssens JP, et al., 1999 74,/with permission of The European Respiratory Society. (C, D) Reused, with permission, from Woods JC, et al., 2006 194/with permission from John Wiley & Sons, Inc.
Figure 2. Figure 2. This figure presents the mechanical properties of normal, aging, and emphysematous lung tissue. Stress‐strain curves of lung parenchymal strips and model fits from normal, aged, and emphysematous subjects. (A) Comparison of normal (5 months) and aged (21 months) mouse stress‐strain curves and the corresponding model fits. (B) Stress‐strain curves calculated from the force‐extension data published in Ref. 161 corresponding to lung tissues of a normal 29‐year‐old human subject and an 80‐year‐old patient with obstructive lung disease. (C) Stress‐strain curves from normal and elastase‐treated mice from Ref. 161 together with their corresponding model fits. Data and graphs were obtained with permission. (A) Reused, with permission, from Bou Jawde S, et al., 2020 20 with “20, figure 7 (p. 8)/Frontiers Media S.A/Licensed under CC BY 4.0”. (B) Reused, with permission, from Sugihara T, et al., 1971 161 with “161, figure 1 (p. 875)/American Physiological Society”. (C) Reused, with permission, from Sugihara T, et al., 1971 161.
Figure 3. Figure 3. This figure shows a schematic diagram of the alveolar microenvironment in the healthy young adult lung. Left: A 2‐dimensional representation of the alveolar septal wall network showing alveolar epithelial type I (AEI) and type II (AEII) cells. A set of mechanical forces (F1, F2, …, Fn) acts on the septal wall network, holding it in a prestretched state corresponding to FRC. Right: A zoom into a single septal wall showing various cell types with their nuclei (white circle/ellipse), types I, III, and IV collagen, elastic fibers, proteoglycans, and glycosaminoglycans (GAGs) including hyaluronan.
Figure 4. Figure 4. This figure demonstrates the kind of changes in the septal wall that takes place due to aging. These include thickened walls and basement membrane, thicker and straighter collagen fibers, fragmented elastic fibers, reduced PG and GAG content, aged and possibly senescent cells, and increased mechanical forces.
Figure 5. Figure 5. This figure demonstrates the typical changes in the septal walls due to emphysema. These alterations are superimposed on the aging septal walls including heterogeneous damaged walls, ruptured fibers and exposed fragments, more inflammatory cells, enzymes, cytokines, and heterogeneous forces among the walls.
Figure 6. Figure 6. This figure is a conceptual representation of the interactions between aging and emphysema


Figure 1. This figure illustrates the alveolar structure in human lungs from (A) a normal 29‐year‐old subject, (B) a 100‐year‐old subject without emphysema, (C) a patient with mild emphysema, and (D) a patient with severe emphysema. The red arrow on panel C indicates a site of rupture. (A, B) Reused, with permission, from Janssens JP, et al., 1999 74,/with permission of The European Respiratory Society. (C, D) Reused, with permission, from Woods JC, et al., 2006 194/with permission from John Wiley & Sons, Inc.


Figure 2. This figure presents the mechanical properties of normal, aging, and emphysematous lung tissue. Stress‐strain curves of lung parenchymal strips and model fits from normal, aged, and emphysematous subjects. (A) Comparison of normal (5 months) and aged (21 months) mouse stress‐strain curves and the corresponding model fits. (B) Stress‐strain curves calculated from the force‐extension data published in Ref. 161 corresponding to lung tissues of a normal 29‐year‐old human subject and an 80‐year‐old patient with obstructive lung disease. (C) Stress‐strain curves from normal and elastase‐treated mice from Ref. 161 together with their corresponding model fits. Data and graphs were obtained with permission. (A) Reused, with permission, from Bou Jawde S, et al., 2020 20 with “20, figure 7 (p. 8)/Frontiers Media S.A/Licensed under CC BY 4.0”. (B) Reused, with permission, from Sugihara T, et al., 1971 161 with “161, figure 1 (p. 875)/American Physiological Society”. (C) Reused, with permission, from Sugihara T, et al., 1971 161.


Figure 3. This figure shows a schematic diagram of the alveolar microenvironment in the healthy young adult lung. Left: A 2‐dimensional representation of the alveolar septal wall network showing alveolar epithelial type I (AEI) and type II (AEII) cells. A set of mechanical forces (F1, F2, …, Fn) acts on the septal wall network, holding it in a prestretched state corresponding to FRC. Right: A zoom into a single septal wall showing various cell types with their nuclei (white circle/ellipse), types I, III, and IV collagen, elastic fibers, proteoglycans, and glycosaminoglycans (GAGs) including hyaluronan.


Figure 4. This figure demonstrates the kind of changes in the septal wall that takes place due to aging. These include thickened walls and basement membrane, thicker and straighter collagen fibers, fragmented elastic fibers, reduced PG and GAG content, aged and possibly senescent cells, and increased mechanical forces.


Figure 5. This figure demonstrates the typical changes in the septal walls due to emphysema. These alterations are superimposed on the aging septal walls including heterogeneous damaged walls, ruptured fibers and exposed fragments, more inflammatory cells, enzymes, cytokines, and heterogeneous forces among the walls.


Figure 6. This figure is a conceptual representation of the interactions between aging and emphysema
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Article Title: Remodeling of the Aged and Emphysematous Lungs: Roles of Microenvironmental Cues
 

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Béla Suki, Jason H.T. Bates, Erzsébet Bartolák‐Suki. Remodeling of the Aged and Emphysematous Lungs: Roles of Microenvironmental Cues. Compr Physiol 2022, 12: 3559-3574. doi: 10.1002/cphy.c210033