The extracellular matrix of the lung and its role in edema formation

Abstract

The extracellular matrix is composed of a three-dimensional fi ber mesh fi lled with different macromolecules such as: collagen (mainly type I and III), elastin, glycosaminoglycans, and proteoglycans. In the lung, the extracellular matrix has several functions which provide: 1) mechanical tensile and compressive strength and elasticity, 2) low mechanical tissue compliance contributing to the maintenance of normal interstitial fluid dynamics, 3) low resistive pathway for an effective gas exchange, d) control of cell behavior by the binding of growth factors, chemokines, cytokines and the interaction with cell-surface receptors, and e) tissue repair and remodeling. Fragmentation and disorganization of extracellular matrix components comprises the protective role of the extracellular matrix, leading to interstitial and eventually severe lung edema. Thus, once conditions of increased microvascular fi ltration are established, matrix remodeling proceeds fairly rapidly due to the activation of proteases. Conversely, a massive matrix deposition of collagen fi ber decreases interstitial compliance and therefore makes the tissue safety factor stronger. As a result, changes in lung extracellular matrix signifi cantly affect edema formation and distribution in the lung.

Role of the extracellular matrix in the genesis of ventilator-induced lung injury

“…Fig. 1a, [2][3][4]). The ECM is a dynamic structure, and equilibrium between synthesis and degradation of its components is required for homeostasis.…”

“…Although many proteases are able to cleave ECM molecules, the family of matrix metalloproteinases (MMPs) are likely to be the normal, physiologically relevant mediators of degradation of ECM components [4]. Many ECM functions are well described, but the role of ECM components in the pathogenesis of ventilator-induced lung injury (VILI) needs to be better clarified [2].…”

“…Some authors have shown that ventilation under physiologic tidal volumes (6-8 ml/kg) for a few hours induces proteoglycan fragmentation from the alveolar septa, which is not associated with activation of systemic or tissue MMPs, lung edema, inflammation, or collagen fiber deposition [2,6].…”

“…Fragmented PGs modify the pulmonary inflammatory response and leukocyte migration through several mechanisms, including (1) the ability of soluble PGs or GAG fragments to activate Toll-like receptor signaling pathways and downstream secretion of proinflammatory mediators; (2) their highly specific binding, sequestration, and interaction with cytokines, chemokines, and growth factors; (3) the ability of PGs and hyaluronan to facilitate leukocyte adhesion and sequestration; and (4) the interactions between PGs and matrix MMPs, which alter the function of these proteases [2,4]. Therefore, fragmentation of GAGs and breakdown of PGs may have an impact on the development of the inflammatory response seen in VILI.…”

Ventilation-induced lung injury exists in spontaneously breathing patients with acute respiratory failure: We are not sure

“…We will not therefore consider here other situations such as pneumonia or deterioration of hemodynamic-related lung edema, which may be associated with mechanical ventilation or spontaneous breathing, but are not necessarily linked to the mechanical forces. The mechanical lesions develop in the interstitial space as microfractures of the matrix [4] or of the capillary walls [5,6]. In fact, when the polymers composing the extracellular matrix are overstretched, some of the molecular bonds will break, generating polymers of lower molecular weight, which in turn, via toll receptors, may activate the inflammatory cascade [7].…”