Injury and Repair

Introduction

The pathogenesis of many pulmonary diseases involves the processes of lung injury and repair, and indeed maintenance of normal lung homeostasis involves cycles of ongoing subclinical microinjury and repair. Injury can be viewed at different levels from the context of whole-organ function or at the level of individual cells or molecules. Similarly, repair can be considered at several levels. Repair can be considered as a sequence of pathologic processes as in repair of a skin wound, at the level of cell replacement, at the level of patching of holes in plasma membranes, or at the level of molecules broken down in the proteosome and replaced by de novo synthesis. Given the complexity of these processes, we provide our definition of the terms injury and repair with the aim of limiting what would otherwise be an exhaustive discussion. In this chapter we will focus on the cellular injury resulting in the dysfunction or death of cells that underlies the pathogenesis of many pulmonary diseases. Injury to any of the different cell types residing in the lung can ultimately lead to organ dysfunction (for a review of lung structure, see Chapter 1 ). A broad concept of lung repair includes processes by which the function of the injured lung is restored to normal. In regard to reparative processes, we will focus on the cellular aspects of repair, including replacement of destroyed cells and restoration of normal cellular function.

Lung Injury and Repair during Homeostasis

As a major portal to the environment, the lung is continuously exposed to a vast array of chemical and biologic agents that can cause cellular dysfunction or even death. Acute episodes of injury to the lung, as a result of viral infection or chemical exposures, result in transient alterations in lung function. Repair therefore can be defined as restitution of the cells, and thus of the lung, to the preinjury level of structure and function. Normal repair returns the lung to a healthy state that is capable of responding to subsequent injuries. The response of the lung to repeated injury and repair is shown in Figure 15-1 . Normal aging is manifest by steady and progressive declines in cell number and/or function and in overall lung function ( Fig. 15-1 , straight blue line), in part due to episodes of recurrent microinjury and decreased capacity of the epithelium or endothelium to heal itself. Normal repair can return the lung function to its prior state ( Fig. 15-1 , fluctuating blue line). Faulty repair leads to episodic loss of function that ultimately results in respiratory failure ( Fig. 15-1 , orange line).

Lung Injury and Repair during Disease

Many common pulmonary disorders, such as chronic obstructive pulmonary disease (COPD), interstitial lung disease, asthma, cystic fibrosis, and the acute respiratory distress syndrome (ARDS), are characterized by cellular injury and faulty repair resulting in clinically significant physiologic abnormalities. The intensity and duration of the insult contribute to the time of onset of symptoms and the chronicity of disease. In ARDS, a severe insult causes widespread lung injury and respiratory failure in hours to days. By contrast, in COPD, years of exposure to the offending agent (usually cigarette smoke in the developed world and biomass fuels in developing countries) results in slowly progressive loss of respiratory function. Patients with interstitial lung disease often have a stuttering course with periods of rapidly declining lung function interspersed with periods of relative quiescence. Importantly, in addition to injury, dysfunctional repair and “remodeling” contribute to the pathogenesis and clinical course of lung diseases, including COPD, asthma, interstitial lung disease, and fibroproliferative ARDS.

Lung Injury

The pathogenesis of many lung diseases involves an exogenous (e.g., inhaled toxin, allergen, infectious agent) or endogenous (inflammation or autoimmune) agent causing cellular dysfunction or death. In COPD, inhaled toxins such as those that make up cigarette smoke initiate processes that culminate in epithelial and endothelial cell death, as well as destruction of extracellular matrix, the scaffolding of the lung. In asthma, allergens, environmental pollutants, pathogens, and the inflammatory response to these agents induce injury to the bronchial epithelium. Pulmonary fibrosis is thought to reflect repetitive injury to the lung epithelium interspersed with periods of relative quiescence.

To illustrate the processes involved in lung injury, we will focus on inflammatory lung injury in ARDS. An extensive review of the causes, pathogenesis, clinical manifestations, and treatment of ARDS is included in Chapter 100 . Briefly, ARDS is defined as the acute onset (within 1 week of the inciting event) of hypoxemia and bilateral opacities on chest imaging attributable to noncardiogenic (increased permeability) pulmonary edema. The severity of ARDS is graded according to the ratio (“P/F ratio”) of the partial pressure of oxygen in the arterial blood to the fractional concentration of oxygen in the inspired air, with a P/F ratio of 200 to 300 defined as “mild,” 100 to 200 defined as “moderate,” and less than 100 defined as “severe.” ARDS is a heterogeneous syndrome rather than a single disease, and predisposing causes include pneumonia, extrapulmonary sepsis, inhalational injury, aspiration, injurious (high tidal volume) mechanical ventilation, pancreatitis, trauma, and blood transfusion. In addition to the acute medical condition, risk factors for the development of ARDS include acquired disorders such as alcohol abuse or cigarette smoking and genetic determinants such as certain genetic polymorphisms ( Fig. 15-2 ). Treatment of ARDS is mainly supportive and includes lung protective (low tidal volume) mechanical ventilation and a conservative fluid management strategy.

Epithelia and endothelia form selective barriers separating various body compartments of different composition from each other or the body from the environment. This barrier function depends on the presence of an intact layer of viable cells as well as the intercellular junctions that link adjacent cells, thus restricting the movement of fluid, ions, and macromolecules. In the healthy lung, the epithelium due to its tight intercellular junctions is the major barrier for passive fluid leak into the alveolar spaces, and, in addition, there is active fluid removal from the alveolar space via the action of specialized ion pumps and transporters in the epithelial cells. In ARDS, compromise of the selective barriers, epithelial as well as endothelial, either via disassembly of intercellular junctions or via death and sloughing of cells, results in an increase in lung permeability and the influx of protein-rich edema fluid, which leads to refractory hypoxemia and bilateral infiltrates on chest radiographs. Cellular dysfunction, such as impaired fluid transport and decreased surfactant production, further contributes to the impaired lung compliance and gas exchange abnormalities.

In ARDS, epithelial and endothelial injury is largely attributable to excessive and dysregulated inflammation ( Fig. 15-3 ) (see Chapter 100 ). In the case of pneumonia, the most common cause of ARDS, microbial products are recognized by resident lung cells, which in turn secrete chemoattractants that recruit inflammatory cells, initially neutrophils, into the lungs. Chemoattractants stimulate neutrophil actin assembly, resulting in stiffening and retention of neutrophils in the pulmonary capillaries. This is followed by intercellular adhesion molecule–mediated adhesion to the endothelium, a process that requires heparanase-mediated cleavage of the glycocalyx, egress from the bloodstream, and transmigration across the epithelium into the air spaces. Neutrophils contain potent antimicrobial compounds, including oxidants, proteinases, and cationic peptides. During immune surveillance or a normal immune response, neutrophils ingest (phagocytose) microorganisms and release these antimicrobial compounds directly into the phagosome. Neutrophil influx into the lungs under most circumstances does not result in tissue injury. However, during excessive and dysregulated inflammation in ARDS, large numbers of activated neutrophils release proteolytic enzymes and oxidants into the extracellular space, causing tissue injury. For example, neutrophil elastase, although inherently antimicrobial and critical for host defense, has been shown to cause injury not only to the extracellular matrix in COPD but also to the alveolar capillary membrane in ARDS. Importantly, neutrophil elastase can cause both a disruption of intercellular junctions and death of endothelial and epithelial cells. ARDS patients have elevated levels of elastase in their bronchoalveolar lavage fluid and plasma, and these levels correlate with the severity of lung injury. Unfortunately, pharmacologic agents that inhibit neutrophil elastase have not proven to be effective in the treatment of ARDS.

In addition to neutrophil elastase, other serine proteases, matrix metalloproteinases (MMPs) and cysteine proteinases are released by inflammatory cells and contribute to tissue destruction during lung injury. Increased levels of MMPs, derived from both neutrophils and macrophages, are present in patients with ARDS and contribute to lung injury. The mechanisms by which MMPs cause lung injury have not been fully elucidated. They are known to degrade junctional proteins in both epithelial and endothelial cells and induce cell death, although the latter is dependent on the cell type and specific MMP. Conversely, some MMPs promote survival of the lung epithelium, and others may attenuate injury or even promote repair.

Defensins are cationic peptides released from inflammatory cells that have potent antimicrobial properties. As with other inflammatory mediators, defensins are released into the extracellular space in ARDS and can cause lung injury, including endothelial and epithelial cell death and noncytotoxic injury. Similar to proteinases, in certain contexts, defensins may also promote lung repair.

In addition to proteinases and antimicrobial peptides, oxidants, including reactive oxygen and nitrogen species, are released by inflammatory cells during ARDS and contribute to tissue injury, including epithelial and endothelial cell death and disruption of tight junctions. Although the lung possesses potent endogenous antioxidant mechanisms, which serve to limit injury, in ARDS these mechanisms are overwhelmed by the large amount of reactive species generated. Additionally, oxidants can potentiate proteinase-induced lung injury, in part by inactivating antiproteinases. Finally, lipid mediators and another recently recognized antimicrobial weapon, neutrophil extracellular traps, can cause epithelial and endothelial injury.

Although much of the early injury to the alveolar capillary membrane is attributable to neutrophils (polymorphonuclear leukocytes) and their mediators, polymorphonuclear leukocytes cannot be the only perpetrators of lung injury because ARDS can develop in neutropenic patients. Recruitment of monocytes to the lungs follows the initial neutrophilic response in ARDS. In contrast to resident alveolar macrophages, which tend to have anti-inflammatory functions, recruited macrophages secrete proinflammatory mediators, including cytokines, chemokines, and lipids, that propagate the inflammatory response. Recruited macrophages also release toxic mediators, including reactive oxygen and nitrogen species, MMPs, tumor necrosis factor (TNF)-α, vascular endothelial growth factor, and interferon-β, which may enhance host defense but also induce tissue injury. In addition, recruited macrophages also play a critical role in both tissue repair and the resolution of inflammation (see later). The role of macrophages in lung inflammation, injury, and repair is further reviewed in Chapter 12 . Finally, in addition to neutrophils and macrophages, platelets, coagulation factors, products of infectious agents, inhaled toxins, oxygen, and mechanical forces all can contribute to injury to the alveolar capillary membrane. Indeed, a diverse array of mechanisms, mediators, and signaling pathways has been implicated in lung injury. Because the spectrum of injurious agents in ARDS is so broad, it is not surprising that pharmacologic strategies to block a single pathway or class of mediators have been ineffective.

Having reviewed the pathogenic agents that induce lung injury, we will now focus on exploring what constitutes lung injury. As mentioned earlier, we define injury as cellular dysfunction or death. Although cellular dysfunction in ARDS includes impaired production of surfactant, which is critical for lung compliance and important in host defense, we will focus here on the cellular dysfunction and death that contribute to increased lung permeability. In inflammatory lung injury the cellular dysfunction that contributes to edema formation includes (1) disruption of intercellular junctions that are responsible for maintaining the barrier function of the endothelium and epithelium and (2) impaired active fluid transport that is responsible for fluid reabsorption and maintenance of dry air spaces. Transient opening and closing of intercellular junctions is necessary for the transmigration of immune cells during immune surveillance or during a normal immune response and can take place without compromising barrier function. However, in ARDS, intercellular junctions of the endothelium and epithelium are disrupted, resulting in enhanced paracellular permeability, which contributes to the flooding of the alveolar spaces with edema fluid. This alveolar flooding is exacerbated by impaired function of the epithelial Na ⁺/K ⁺pumps and epithelial Na ⁺channels that are responsible for fluid reabsorption. Attempts at stimulating fluid clearance with β-agonists have not improved outcomes in ARDS, perhaps because the barrier must be restored before the pumps can be effective (see Chapter 9 ).

In addition to the disruption of intercellular junctions, severe lung injury in ARDS and other lung diseases is characterized by cell death. In ARDS, inflammatory mediators induce death of endothelial cells as well as alveolar epithelial type I (ATI) cells, leaving surviving alveolar epithelial type II (ATII) cells, which are more resistant to injury, populating a largely denuded basement membrane. This dramatic injury to the alveolar epithelium engendered the term diffuse alveolar damage , which describes the histologic appearance of lungs taken from patients who died of ARDS.

Endothelial and epithelial cells can be lost via necrotic cell death or via programmed cell death, the latter termed “apoptosis.” Originally a morphologic definition, apoptosis might best be defined not only on the basis of nuclear condensation and characteristic DNA fragmentation but also based biochemically on activation of intracellular proteases termed “caspases.” Many recent reviews address the various mechanisms underlying apoptosis. However, it is important to note that there are two major pathways leading to apoptosis: the intrinsic pathway, involving signaling from the mitochondria; and the extrinsic pathway, deriving from signals generated from external stimulation of “death” receptors. In “normal” adult humans or experimental animals, snapshot analyses of lung tissue indicate only small scattered examples of replicating cells or of cells undergoing apoptosis. Because apoptotic cells are actively extruded from epithelial surfaces and cleared rapidly, the fact that evidence of apoptosis is detectable at all may indicate a higher degree of cellular turnover than previously thought. Early reports suggested that mitochondrial regulation of alveolar epithelial apoptosis may be induced by the proapoptotic BCL2 family member BAX and p53. Additional literature suggests that death receptors of the TNF receptor family such as FAS mediate apoptosis via the extrinsic pathway. Both FAS and FAS ligand levels are elevated in the edema fluid of ARDS patients, they induce epithelial cell apoptosis in a manner dependent on their modulation by oxidants and proteases, and elevated levels are predictive of worse clinical outcomes. In animal models of lung injury, FAS and TNF-related apoptosis-inducing ligand induce epithelial cell apoptosis, and inhibition of apoptosis improves survival. Conversely, hyaluronan, while promoting inflammation, attenuates epithelial cell apoptosis. Apoptotic epithelial cells are engulfed by both professional phagocytes (macrophages) and other epithelial cells.

In ARDS, lung cells can also die by necrosis, which leads to disruption of cell membranes with subsequent release of cellular contents that may be injurious. Causes of epithelial and endothelial necrosis in ARDS include physical effects of acid from inspiration of stomach contents, inhalation of toxic materials or fumes, infection with lytic viruses or bacterial products, hyperoxia, and mechanical disruption of cell membranes during mechanical ventilation. In sum, cell death is a major mechanism of lung injury, resulting in denudation and contributing to lung permeability and the massive influx of edema fluid, despite the existence of endogenous protective mechanisms.

Lung Repair

The ability of the lung to withstand considerable damage and repair itself enables recovery and survival from a variety of noxious stimuli. For the purpose of this chapter, we define repair broadly as processes by which the function of the injured lung is restored to normal . Repair of the lung after acute injury requires restitution of the endothelial and epithelial barriers, clearance of edema fluid, and the resolution of inflammation. In the case of ARDS, survival depends on repair of the injured lung, although some survivors do not regain normal lung function.

Endothelial Repair

Given that lung injury involves disruption of intercellular junctions and cell death, repair requires repopulation of the denuded basement membrane and reassembly of these junctions. Elegant work has demonstrated the importance of sphingosine-1-phosphate, released from activated platelets, in stimulating reassembly of endothelial intercellular junctions via Rho- and Rac-dependent cytoskeletal rearrangement. This process is dependent on αvβ3 integrin. In addition, the SLIT/ROBO mechanism was recently identified to stabilize the endothelial adherens junctions by promoting p120-catenin/E-cadherin association. Stabilization of actin cytoskeleton by the Rho GTPases enhances endothelial barrier integrity. Additional information on the regulation of endothelial function is found in Chapter 6 .

Epithelial Repair

Although the alveolar epithelium is more resistant to injury than is the endothelium, increased epithelial permeability is required for the development of airspace edema. Conversely, repair of the alveolar epithelium is critical for the resolution of edema, restoration of functions such as surfactant production and ion and fluid transport, and clinical outcome. In the epithelium, keratinocyte growth factor (KGF), interferon-γ, phosphatase and tensin homologue, epidermal growth factor, and c-Met are protective of tight junctional integrity during lung injury by mechanisms that involve cytoskeletal reorganization rather than enhanced expression of junctional proteins. Regulation of tight junctions in the alveolar epithelium after injury is an important and active area of investigation.

If the severity of the injury is such that there has been extensive cell death, the endothelium and epithelium must be repopulated. As an illustration of the mechanisms involved, we will focus on re-epithelialization of the denuded alveolar epithelium after injury. The injured alveolar epithelium re-epithelializes in stages, many of which are orchestrated by the ATII cell, the “defender of the alveolus.” These stages include (1) ATII cell spreading and migration, (2) ATII cell proliferation, (3) differentiation of ATII cells into ATI cells to restore a normal constitution of the alveolar epithelium, and finally (4) if the injury is extensive, migration and proliferation of bronchiolar stem cells to repopulate the injured alveolus ( Fig. 15-4 ; ). Recent work has identified various stem cell populations that likely contribute to this repair. Epithelial injury and repair promotes the activation of fibroblasts, which although important for physiologic wound repair, under certain circumstances, when dysregulated, can result in fibrotic lung disease. Each of these phenomena will be discussed in more detail in the following sections.

Cell Spreading and Migration

After death of alveolar epithelial cells, surviving ATII cells likely spread and migrate onto the denuded basement membrane. Although this has not been directly observed in the alveolar epithelium in vivo, cell spreading and migration is certainly the fastest mechanism for resealing the leaky epithelium based on in vitro observations and on observations of the importance of these phenomena in wound repair of other organs. Cell migration depends on tightly regulated assembly of the cytoskeleton leading to protrusion of “lamellipodia” and “filopodia” from the leading edge followed by contractile forces that release the rear edge from the extracellular matrix, processes that depend on the Rho GTPases. In the lung epithelium, cell spreading and migration after injury are triggered by soluble factors such as KGF, transforming growth factor (TGF)-α, TGF-β, interleukin-1β, and cytokine-induced neutrophil chemoattractant 2. Cell migration is further mediated by signaling pathways, including Rac1/TIAM1, phosphatase and tensin homologue, β-catenin, syndecan-1, adenosine triphosphate and dual oxidase 1, and vimentin, as reviewed elsewhere. Integrins, which are up-regulated in the alveolar epithelium after injury, contribute to cell migration via interactions with both the actin cytoskeleton and the extracellular matrix. The production of extracellular matrix as well as MMPs are critical to cell migration. MMPs enhance wound healing by cleaving cell-cell and cell–extracellular matrix adhesion molecules, activating chemokines and growth factors by proteolysis, and degrading the provisional matrix. Notably, cyclic stretch, imposed by mechanical ventilation during repair after ARDS, impedes cytoskeletal reorganization during cell spreading.

Cell Proliferation

In addition to cell spreading and migration, the denuded epithelial basement membrane is repopulated through the proliferation of surviving ATII cells, which accounts for the epithelial cell hyperplasia observed on histologic samples. In animal models, significant acute lung injury resulting in cell death triggers alveolar epithelial cell proliferation. Factors that promote ATII cell proliferation after injury include the heparin-binding growth factors KGF, hepatocyte growth factor, and heparin-binding epidermal growth factor, an effect that is significant enough to decrease mortality in animal models of lung injury, although the protective role of KGF may in part be attributable to enhanced epithelial cell survival. Other factors and pathways implicated in ATII cell proliferation after injury include granulocyte-macrophage colony-stimulating factor, which is also protective against injury, β-catenin signaling, macrophage migration inhibitory factor, and FOXM1. Proliferating ATII cells ultimately differentiate into ATI cells or die by apoptosis and are subsequently removed by macrophages or neighboring ATII cells. Mechanisms regulating differentiation of ATII cells into ATI cells are not well understood, but this process is promoted by TGF-β and insulin-like growth factor-I. The classic concept has been that ATII cells are responsible for alveolar repair by spreading into the denuded area, proliferating, and ultimately differentiating into ATI cells. However, at least in vitro, transdifferentiation is reversible. In this regard, a recent in vitro study reveals that ATI cells are also capable of cell spreading, migration, proliferation, and expression of surfactant protein-C, suggesting that these cells may also play a role in repair.

Role of Fibroblasts in Repair

Normal repair depends on epithelial-mesenchymal interactions, including the proliferation of subepithelial fibroblasts with deposition of granulation tissue. Mesenchymal cells provide signals and specific growth factors such as hepatocyte growth factor and KGF to epithelial cells to facilitate repair. By contrast, after repetitive and/or nonresolving injury, dysfunctional epithelial repair results in fibroblast recruitment, proliferation, and differentiation into myofibroblasts with deposition of excessive extracellular matrix composed of collagen and fibronectin. Severe or repetitive epithelial injury with dysfunctional repair can promote fibroproliferative responses in ARDS and other lung diseases, including idiopathic pulmonary fibrosis, asthma, and COPD, a topic which is reviewed in detail elsewhere. Although cytokines and growth factors that induce physiologic repair can prevent fibrosis under certain circumstances, under other circumstances, these same factors may actually promote fibrosis, underscoring the importance of context in lung repair. Therefore caution is indicated when considering therapeutic intervention aimed at accelerating repair of the injured lung, so as not to induce fibrosis. Epithelial “regeneration,” the restoration of normal lung architecture, must be distinguished from “simple repair,” which can include repopulation by abnormal cell types and scar formation.

Resolution of Inflammation

Ultimately, the inflammatory response must resolve in order to halt ongoing injury to the lung and allow reparative processes to proceed. An important step for resolution of inflammation is the apoptotic clearance of neutrophils. Neutrophils undergo apoptosis, a noninflammatory, nonimmunogenic form of cell death during which they retain their toxic mediators within their plasma membrane. This is in contrast to a necrotic cell death, in which neutrophils disintegrate with release of their intracellular constituents, including toxic and proinflammatory mediators, resulting in prolongation of the inflammatory response. Neutrophil apoptosis can be delayed by proinflammatory mediators such as granulocyte-macrophage colony-stimulating factor and endotoxin and by hypoxia, but it is enhanced by T regulatory lymphocytes in a TGF-β–dependent manner. Delayed neutrophil apoptosis is mediated by complex intracellular signaling pathways that involve hypoxia inducible factor-1 and cyclin-dependent kinases signaling through the antiapoptotic BCL2 family member MCL1. Apoptotic neutrophils are cleared by macrophages in a phagocytic process termed “efferocytosis” without release of toxic intracellular contents. Efferocytosis depends on the recognition of “eat me” signals, including phosphatidylserine and calreticulin, that are displayed on the apoptotic cell surface by a variety of receptors. This is followed by activation of Rho GTPases, leading to engulfment, which is regulated by the mitochondrial membrane protein UCP2, as well as HMGB1 and urokinase-type plasminogen activator. Efferocytosis results in the release of anti-inflammatory mediators that further promote the resolution of inflammation rather than inducing a proinflammatory macrophage response. Apoptotic neutrophils can also be efferocytosed by myeloid-derived suppressor cells in an interleukin-10–dependent manner. Whereas clearance of apoptotic neutrophils is usually highly efficient, yielding a low number of observable apoptotic cells at any given time, if apoptotic clearance is defective or overloaded, apoptotic neutrophils can undergo secondary necrosis or postapoptotic cytolysis. Thus, impaired neutrophil apoptosis and efferocytosis would prolong the duration of the inflammatory response, likely resulting in chronic inflammatory lung disease. Lipid mediators promote the resolution of inflammation by enhancing neutrophil apoptosis and efferocytosis, as well as through other mechanisms. In addition to neutrophils, inflammatory macrophages must also be cleared during the resolution of lung injury.

Stem Cells, Constitutive Cell Turnover, and Reparative Cell Types

Hierarchies of Reparative Cells

The concept of injury and repair is fundamentally linked to the stem cell attributes of mitotic potential and differentiation capacity. Mitotic potential has two components, the number of times a cell can undergo division and the time at which these cell divisions take place. Differentiation potential is defined in terms of the variety of differentiated cell types that can be generated by an individual mitotic cell. Many of the current concepts about stem and progenitor cell function in the lung derive from studies of airway epithelial cells. Comparatively less in known regarding the identity of long-term stem cells in the alveolar region and even less is known about resident stem and progenitor cells for the diverse lung mesenchymal cell populations. The knowledge of the stem and progenitor cells’ functions in the airway will be used as a foundation to illustrate the basic principles of how stem cells are involved in repair of the injured lung.

Classical Stem Cell Hierarchy

Within a classical stem cell hierarchy ( Fig. 15-5 ), the stem cell is defined as the reparative cell with the greatest mitotic and differentiation potential. A stem cell proliferates indefinitely and thus distributes its mitotic potential over the life span of the organism. These attributes of “stemness” are controlled by interaction of the stem cell with the stem cell microenvironment or niche. The niche serves to protect or sequester stem cells from factors that promote their differentiation. Stem cell division produces two daughter cells whose fate is determined by interactions with the stem cell niche. Symmetrical cell division results in both daughter cells retaining contact with the niche and maintenance of these nascent cells as stem cells. This mechanism, which results in amplification of stem cell number, has been demonstrated in tissues with rapid cell turnover, such as the bone marrow and gut. In contrast, asymmetric cell division results in generation of one daughter cell that maintains contact with the niche and is retained as a stem cell. The second daughter cell then loses contact with the niche and undergoes repeated cell division over a short period of time. This second daughter cell is the founding cell for the transit-amplifying cell population. Transit-amplifying cells are temporary constituents of the niche. They proliferate repeatedly over a short time period and then withdraw from the cell cycle as they commit to a differentiation pathway. Thus transit-amplifying cells serve to increase cell number and are destined to produce terminally differentiated cells. Terminally differentiated cells can have one or more phenotypes and constitute the majority of cells within a given tissue. These cells are largely responsible for conferring the phenotypic characteristics of a specific tissue or organ. Terminally differentiated cells are postmitotic. Thus loss of the terminally differentiated cell population acts as a stimulus for the differentiation of transit-amplifying cells that resupply this population.

Cells Involved in Lung Repair

Progenitor Cell

The term progenitor cell is a collective term used to describe any cell that has the capacity to proliferate. It is commonly used to indicate a cell that is in the process of cell division or has the potential to enter the cell cycle. The functional distinctions among lung progenitor cells are defined in the sections that follow.

Tissue-Specific Stem Cells

A tissue-specific stem cell is a rare cell type that is undifferentiated relative to its progeny. This cell has the capacity for unlimited self-renewal as a consequence of stable interactions with a stem cell niche. In the context of a hierarchy, the stem cell is defined as the reparative cell with the greatest mitotic and differentiation potential. Adult tissue stem cells have a differentiation potential equivalent to the cellular diversity of the tissue in which they reside. Because of the relatively quiescent state of the pulmonary epithelium, lung stem cells are identified as cells that are activated in response to severe cell depletion. As a consequence of this experimental approach, we will review the properties of lung stem cells in the context of severe injury.

Tracheobronchial tissue-specific stem cells have been evaluated in detail in mice. These cells exhibit a low cuboidal to pyramidal morphology and are termed basal cells. Additional studies have suggested that the tracheobronchial tissue-specific stem cell resides within specialized microenvironments located at the submucosal gland duct junction and in intercartilaginous regions of the trachea and bronchial epithelium. In murine bronchioles, tissue-specific stem cells have been identified within neuroepithelial bodies and bronchiolar duct junction microenvironments. These cells are resistant to club cell (Clara)–specific toxicants such as naphthalene and express the molecular marker club cell secretory protein (CCSP). The identity of alveolar stem cells remains incompletely understood. The ATII cell is generally believed to serve this function, although bronchiolar stem cell populations, which express α6β4 integrin, keratin 5, or p63 but not prosurfactant C, may function as alveolar epithelial progenitor cells after injury under certain circumstances.

Facultative Progenitor Cell Pools

A facultative progenitor cell is one that exhibits differentiated features in the quiescent state yet has the capacity to proliferate for maintenance of normal tissue and in response to injury. In contrast with the bone marrow and gut, the lung epithelium is maintained and repaired under most conditions by an abundant, broadly distributed facultative progenitor cell pool. Facultative progenitor cells exist in two states: quiescent and reparative. In the steady state, facultative progenitor cells are nonmitotic and carry out differentiated functions necessary for tissue homeostasis. In response to injury, facultative progenitor cells dedifferentiate, enter the cell cycle, self-renew, and have a context-dependent probability of differentiating into regionally specific differentiated cell types such as ciliated epithelial cells and ATII cells. Examples of facultative progenitor cells in the lung are the club cell in the airway and the ATII cell in the alveolus.

Loss of Regenerative Potential: Depletion of the Facultative Progenitor Cell Pool

Multifunctional properties of pulmonary facultative progenitor cells also limit their ability to repair the injured conducting airway epithelium in the mouse lung. First, the metabolic pathways that allow the club cell to eliminate lipophilic agents also sensitize it to the toxic effects of these compounds. Second, the phenotypic plasticity that is essential to the club cell’s ability to detect and eliminate pathogens may compromise the reparative functions of this cell type. Finally, repeated participation in epithelial repair may deplete the mitotic potential of the facultative progenitor cell pool. Depletion of this cell type would leave the epithelium deficient in both regenerative and differentiated functions and could result in a cascade of changes that contribute to epithelial fragility through loss of cellular autocrine/paracrine protective mechanisms, epithelial hypoplasia, and dysregulation of interactions between the epithelial, mesenchymal, and vascular compartments.

Histologic measures of a low abundance of club cells and CCSP support the concept that the facultative progenitor cell type(s) are depleted in acute lung injury and in chronic lung diseases. These studies suggest that four processes lead to depletion of this critical cell type. First, transition to a mucus-producing cell type may alter both progenitor function and cellular interactions. Within small airways of COPD patients and asthmatics, club cells undergo a metaplastic transition to a mucosecretory phenotype. In severe disease, both club cells and mucosecretory cell types are depleted, and the epithelium becomes hypoplastic. Analysis of colony-forming cells within the human bronchial epithelium demonstrated that human mucous cells are postmitotic cells. These observations suggest that hyperplasia of mucous cells, in the context of acute or chronic lung disease, is a consequence of a phenotypic transition by non–mucus-producing cells.

Second, transition of progenitor cells from a facultative to an obligate progenitor state may also lead to depletion of reparative cells. Increased epithelial proliferation in the lungs of smokers suggests an ongoing injury process and the potential for replicative senescence within the facultative progenitor cell pool. Senescent cells persist and consequently inhibit activation of the remaining reparative cells. Thus senescent cells could compromise differentiated functions while also blocking cell replacement mechanisms.

Third, entry of the facultative progenitor cell into the cell cycle is accompanied by loss of differentiated functions such as secretion of CCSP or production of surfactant. Extensive analysis of CCSP levels in acute and chronic lung disease, including COPD, suggests that differentiated functions of the facultative progenitor cells are compromised and that these cells are a direct target of toxic environmental agents. Thus injuries that activate facultative progenitor cells may adversely affect protective mechanisms and render the epithelium susceptible to further injury.

Finally, defects in cellular maturation may also contribute to a failure to establish the facultative progenitor cell pool or to deplete it after injury. The lung undergoes rapid and extensive maturation during the postnatal period. The maturation process is interrupted by preterm birth and associated oxygen treatment and is attenuated by postnatal exposure to environmental agents, including ozone and side-stream tobacco smoke in term infants. These studies support the concept that failure to establish or maintain an appropriately sized pool of facultative progenitor cells fosters environmentally induced chronic injury and dysfunctional repair cycles characteristic of lung disease. Hypoplasia of bronchial club cells is associated with tissue remodeling characterized by hyperplasia of an alternative progenitor, the basal cell, and consequent squamous metaplasia. In contrast, club and ATII cells are progenitors of the bronchiolar and alveolar epithelium, respectively, although as mentioned earlier, bronchiolar stem cells may repopulate the alveolus, and an alveolar epithelial cell that expresses α6β4 integrin, but not prosurfactant C, may function as an alveolar epithelial progenitor cell after injury. Depletion of either of these cell types leads to epithelial hypoplasia and remodeling of adjacent tissue compartments. Thus changes in function and/or abundance of the facultative progenitor may be the nexus for the complex pathophysiologic alterations in chronic lung diseases.

Gene-Environment Interactions in Lung Injury and Repair

The four Rs (regeneration, repair, remodeling, and replacement) are presented as distinct processes; however, they are actually intricately intertwined responses to acute or chronic lung injury ( Fig. 15-6 ). These relationships are modified by gene-environment interactions, interactions based on the concept that genetic constitution determines the response to deleterious agents within the environment.

Genetic predisposition has been associated with allelic variants that modify cellular susceptibility to environmental agents, including chemical (ozone, naphthalene, cigarette smoke) and microbial (lipopolysaccharides, viral pathogens) agents. Such alleles can sensitize an individual to an initial or repeated injury but can also render him or her resistant to subsequent exposures through induction of tolerance.

Genotype can also be a determinant of the cellular response to an agent. In mice, specific genetic backgrounds are susceptible to metaplastic transitions such as conversion of airway secretory cells into a mucus-producing goblet cell phenotype (e.g., C57BL/6 vs. Balb/c strains of mice). Such transitions are associated with protection of the epithelium from further injury. Alterations in cellular phenotype may also extend to interactions between endogenous lung elements (epithelium, mesenchyme, nerves) and itinerant (recruited) cells such as neutrophils, monocytes, and lymphocytes. Certain inbred strains of mice (e.g., C57BL/6) are more susceptible to bleomycin-induced inflammation and develop transient replacement of alveolar structures with mesenchymal cells resulting in fibrosis. Thus susceptibility to injury and the response to such an insult are determined by multiple factors, including the nature of the agent, dose and route of exposure, exposure history, the host genotype, and epigenetic factors molded by gene-environment interactions.

Does Lung Repair Recapitulate Lung Development?

Numerous signaling processes are known to be involved in lung development including Wnt/β-catenin, notch-delta, sonic hedgehog-patched, fibroblast growth factor–fibroblast growth factor receptor, and bone morphogenetic protein/TGF-β. These pathways are interactive and integrate formation and appropriate differentiation of tissues (epithelium, mesenchyme, vasculature) during lung development. During lung injury and repair, reactivation of many of these pathways has been reported. It is unclear, however, whether these various signaling pathways are integrated and whether this signaling results in productive cell replacement. Indeed, analysis of damaged human lung tissue is descriptive, and thus cause and consequence usually cannot be separated. In contrast, analysis of signaling pathways in animal models relies on elimination of a specific pathway or profound misregulation of the targeted process. Consequently, feedback mechanisms are likely to be disrupted and may result in altered activation/inactivation of parallel or sequential signaling networks. Development of methods to simultaneously monitor alterations in multiple signaling cascades is needed to address this fundamental obstacle to understanding the molecular regulation of reparative processes. Hence at this time it is not known if regulatory pathways that are dominant during development also regulate repair in the adult.

Key Points

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The processes of lung injury and repair underpin the pathogenesis of myriad lung diseases, as well as the normal aging process.
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The mechanisms of injury are rooted in the cellular and molecular changes that initiate structural alterations and lead to compromised lung function. At the tissue and cellular level, exogenous insults and/or inflammatory stimuli result in increased vascular permeability and loss of alveolar epithelial barrier function due to disruption of intercellular junctions and cell death.
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Susceptibility to lung injury is determined by general health, previous exposures, and the individual’s genetic constitution. This “gene-environment interaction” is the cornerstone of research initiatives directed at identification of susceptibility genes and those that modify the response to treatment.
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Lung repair involves restoration of normal cellular composition, lung architecture, barrier function, and gas exchange.
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In response to cellular injury by noxious stimuli such as microbes and toxic compounds, endogenous stem and progenitor cells undergo rapid proliferation and differentiation resulting in repair and regeneration of the injured lung. Under normal circumstances repair of the alveolar epithelium after injury depends on cell spreading, migration, and proliferation of surviving alveolar epithelial type II (ATII) cells, followed by differentiation of ATII cells into ATI cells. However, in severe injury, additional non-surfactant protein C–expressing cells, likely from the bronchioalveolar junction, can repopulate the alveolar epithelium.
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Repetitive epithelial injury and dysfunctional repair can lead to fibroproliferative responses in the airways and parenchyma; fibroproliferative responses are thought to be critical to the pathogenesis of some diseases, including pulmonary fibrosis, COPD, and asthma.
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Ultimately, the inflammatory response must resolve in order to halt ongoing injury to the lung and to allow repair. Inflammatory cells undergo apoptosis and are cleared by macrophages in a phagocytic process termed “efferocytosis.”

Key Readings

Abrams ST, Zhang N, Manson J, et. al.: Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med 2013; 187: pp. 160-169.

Adamson IY, Bowden DH: The type 2 cell as progenitor of alveolar epithelial regeneration: a cytodynamic study in mice after exposure to oxygen. Lab Invest 1974; 30: pp. 35-42.

Bachofen M, Weibel ER: Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest Med 1982; 3: pp. 35-56.

Barkauskas CE, Cronce MJ, Rackley CR, et. al.: Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 2013; 123: pp. 3025-3036.

Beers MF, Morrisey EE: The three R’s of lung health and disease: repair, remodeling, and regeneration. J Clin Invest 2011; 121: pp. 2065-2073.

Berthiaume Y, Lesur O, Dagenais A: Treatment of adult respiratory distress syndrome: plea for rescue therapy of the alveolar epithelium. Thorax 1999; 54: pp. 150-160.

Bertoncello I, McQualter JL: Lung stem cells: do they exist?. Respirology 2013; 18: pp. 587-595.

Caudrillier A, Kessenbrock K, Gilliss BM, et. al.: Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest 2012; 122: pp. 2661-2671.

Chapman HA, Li X, Alexander JP, et. al.: Integrin α6β4 identifies an adult distal lung epithelial population with regenerative potential in mice. J Clin Invest 2011; 121: pp. 2855-2862.

Crosby LM, Waters CM: Epithelial repair mechanisms in the lung. Am J Physiol Lung Cell Mol Physiol 2010; 298: pp. L715-L731.

Gardner A, Borthwick LA, Fisher AJ, et. al.: Lung epithelial wound healing in health and disease. Expert Rev Respir Med 2010; 4: pp. 647-660.

Herridge MS, Tansey CM, Matte A, et. al.: Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011; 364: pp. 1293-1304.

Jamieson AM, Pasman L, Yu S, et. al.: Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science 2013; 340: pp. 1230-1234.

Kumar PA, Hu Y, Yamamoto Y, et. al.: Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell 2011; 147: pp. 525-538.

Martin TR, Hagimoto N, Nakamura M, et. al.: Apoptosis and epithelial injury in the lungs. Proc Am Thorac Soc 2005; 2: pp. 214-220.

Mason RJ, Williams MC: Type II alveolar cell: defender of the alveolus. Am Rev Respir Dis 1977; 115: pp. 81-91.

Matthay MA, Ware LB, Zimmerman GA: The acute respiratory distress syndrome. J Clin Invest 2012; 122: pp. 2731-2740.

Ranieri VM, Rubenfeld GD, Thompson BT, et. al.: Acute respiratory distress syndrome: the Berlin definition. JAMA 2012; 307: pp. 2526-2533.

Serhan CN, Savill J: Resolution of inflammation: the beginning programs the end. Nat Immunol 2005; 6: pp. 1191-1197.

Wansleeben C, Barkauskas CE, Rock JR, et. al.: Stem cells of the adult lung: their development and role in homeostasis, regeneration, and disease. Wiley Interdiscip Rev Dev Biol 2013; 2: pp. 131-148.

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Jul 21, 2019 | Posted by drzezo in CARDIOLOGY | Comments Off

Thoracic Key

Fastest Thoracic Insight Engine

Injury and Repair

Introduction

Lung Injury and Repair during Homeostasis

Lung Injury and Repair during Disease

Lung Injury

Lung Repair

Endothelial Repair

Epithelial Repair

Cell Spreading and Migration

Cell Proliferation

Role of Fibroblasts in Repair

Resolution of Inflammation

Stem Cells, Constitutive Cell Turnover, and Reparative Cell Types

Hierarchies of Reparative Cells

Classical Stem Cell Hierarchy

Cells Involved in Lung Repair

Progenitor Cell

Tissue-Specific Stem Cells

Facultative Progenitor Cell Pools

Loss of Regenerative Potential: Depletion of the Facultative Progenitor Cell Pool

Gene-Environment Interactions in Lung Injury and Repair

Does Lung Repair Recapitulate Lung Development?

Key Readings

References

Related

Stay updated, free articles. Join our Telegram channel

Full access? Get Clinical Tree

Thoracic Key

Fastest Thoracic Insight Engine

Injury and Repair

Introduction

Lung Injury and Repair during Homeostasis

Lung Injury and Repair during Disease

Lung Injury

Lung Repair

Endothelial Repair

Epithelial Repair

Cell Spreading and Migration

Cell Proliferation

Role of Fibroblasts in Repair

Resolution of Inflammation

Stem Cells, Constitutive Cell Turnover, and Reparative Cell Types

Hierarchies of Reparative Cells

Classical Stem Cell Hierarchy

Cells Involved in Lung Repair

Progenitor Cell

Tissue-Specific Stem Cells

Facultative Progenitor Cell Pools

Loss of Regenerative Potential: Depletion of the Facultative Progenitor Cell Pool

Gene-Environment Interactions in Lung Injury and Repair

Does Lung Repair Recapitulate Lung Development?

Key Readings

References

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