Chapter One - The Role of Matrix Metalloproteinases in Development, Repair, and Destruction of the Lungs

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Abstract

Normal gas exchange after birth requires functional lung alveolar units that are lined with epithelial cells, parts of which are intricately fused with microvascular capillaries. A significant phase of alveolar lung development occurs in the perinatal period, continues throughout early stages in life, and requires activation of matrix-remodeling enzymes. Failure to achieve an optimum number of alveoli during lung maturation can cause several untoward medical consequences including disabling obstructive and/or restrictive lung diseases that limit physiological endurance and increase mortality. Several members of the matrix metalloproteinase (MMP) family are critical in lung remodeling before and after birth; however, their resurgence in response to environmental factors, infection, and injury can also compromise lung function. Therefore, temporal expression, regulation, and function of MMPs play key roles in developing and maintaining adequate oxygenation under steady state, as well as in diseased conditions. Broadly, with the exception of MMP2 and MMP14, most deletional mutations of MMPs fail to perturb lung development; however, their individual absence can alter the pathophysiology of respiratory diseases. Specifically, under stressed conditions such as acute respiratory infection and allergic inflammation, MMP2 and MMP9 can play a protective role through bacterial clearance and production of chemotactic gradient, while loss of MMP12 can protect mice from smoke-induced lung disease. Therefore, better understanding of the expression and function of MMPs under normal lung development and their resurgence in response respiratory diseases could provide new therapeutic options in the future.

Introduction

Pulmonary diseases comprise common medical conditions that are associated with increased morbidity and mortality worldwide. Since the latter part of the 20th century, tobacco smoking has become the most common cause of lung disease worldwide and the third leading cause of death in the United States.1, 2 Other risk factors for chronic lung disease development include environmental pollutants that arise from rapid industrial growth in highly populated countries that produce massive quantities of particulate matter less than 2.5 μm in size (PM2.5).3 Other types of air pollution lead to gender-specific lung dysfunction. For example, involuntary exposure to biomass fuel from indoor cooking predominantly affects women, whereas coal mining and other heavy labor-intensive occupations affect men.4, 5, 6 Multiple genetic risks and environmental factors can predispose individuals to develop early-onset asthma and chronic obstructive pulmonary disease (COPD); however, some commonly inherited genetic mutations (e.g., cystic fibrosis (CF) and primary ciliary dyskinesia) can cause lung disease independent of the environment.7, 8 Fibrotic and destructive lung parenchymal diseases secondary to known and unknown genetic mutations (e.g., idiopathic pulmonary fibrosis, Birt Hogg Dube syndrome, and tuberous sclerosis), as well as vascular disorders (e.g., hereditary hemorrhagic telangiectasia), can be modified by environmental exposures and/or show gender-specific traits.9 Other less appreciated causes (e.g., immune dysfunction) result in recurrent childhood infections and prevent normal lung development.10

The gas exchange functional units in the lungs, known as alveoli, are highly developed intricate structures that provide oxygenated hemoglobin at rest and rapidly increase oxygen-carrying capacity as demanded at maximal activity. Alveoli are supported by respiratory epithelial type I and endothelial cells whose membranes fuse to provide efficient and effortless exchange of oxygen and carbon dioxide at rest. Under normal conditions, and despite its essential role in all living organisms, gas exchange remains a passive and autonomous body function.11 When a portion of alveoli is lost and normal lung architecture is disturbed, quiet breathing at rest can often remain preserved. Therefore, because of the minimal amount of work required for breathing at rest, significant respiratory dysfunction often presents late in the disease course. Only when individuals require high ventilation for increased exercise endurance, significant disability can be unmasked. Interruption of gas exchange due to the loss of alveoli in response to an acute insult can be transient; however, recurrent insult likely results in permanent alteration of the lung architecture and function. Once compromised, alveolar loss can limit oxygenation and increase the work required by the heart, which can further result in cardiopulmonary disability and early death. Among the factors that promote loss of lung function, recruitment of inflammatory cells and their secreted mediators in the lung can adversely affect lung structure and significantly alter the course of lung function.

In particular, the matrix metalloproteinase (MMP) family of zinc-dependent endopeptidases, capable of degrading extracellular matrix (ECM) and other substrates, are intricately involved in the inflammation and tissue restructuring that play key roles in the pathogenesis of many lung diseases.12 Normal expression of MMPs and their endogenous inhibitors—tissue inhibitors of MMPs (TIMPs)—in the lung is tightly regulated, showing upregulation in initial lung development, remodeling in response to tissue injury, and host defense against pathogens.13, 14, 15 The regulation of MMP activity occurs by four processes: MMP gene expression at the transcriptional and translational levels, vesicle trafficking and secretion, activation of latent proforms and deactivation by other proteinases, and complexing with specific TIMPs.16 Here, we discuss current known facts about MMP activity in lung development, the normal wound repair response, and the pathogenesis of pulmonary diseases.

Section snippets

Lung Development

From the almost solid respiratory progenitors, the lungs dynamically develop into air-filled tissue with vast epithelial surface area and millions of alveoli. The multistep process of lung development begins when the laryngotracheal groove in the endoderm epithelium separates from the primitive esophagus to form two bronchial buds. These buds then go through several generations of stereotypic branching morphogenesis to give rise to the bronchial tree. After 16 generations, the reproducible

MMPs in Lung Repair Responses to Injury

As with the skin, the normal lung epithelium is able to activate repair and regeneration pathways following injury caused by bacterial or viral infections, exposure to harmful particulates, allergic reactions, or physical trauma. The lung injury response is separated into three stages: (1) initiation of the injury from intrinsic and/or extrinsic factors that cause epithelial damage or dysfunction, leading to the activation of alveolar epithelial cells; (2) amplification of inflammatory effector

MMPs in Destruction of the Lung

Many current models of disease pathogenesis of the lungs focus on dysregulated wound repair and altered epithelial–mesenchymal signaling after recurrent injury to the epithelium.56 Upon injury, lung epithelium may either initiate the required repair and regeneration response for the appropriate repopulation of damaged epithelial cells or proceed with an aberrant remodeling and differentiation process that leads to disease.20 Contributing factors that lead to destruction, rather than repair,

Concluding Remarks

The MMPs belong to a highly conserved family of proteinases and play diverse biological functions in the lungs. Normal lung development required a well-orchestrated spatial and temporal expression of MMPs, while aberrant expression of different members of MMPs can induce destructive and/or fibrotic changes in the lungs. MMP family members share variable degrees of sequence homology and may have overlapping substrate specificity, but their cell-specific expression in response to different

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