SciELO - Scientific Electronic Library Online

vol.29 issue4The value of cytology and pleural biopsy in the differential diagnostic of nonspecific pleural effusionsQuestion: what is the diagnosis? author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand



  • Article in xml format
  • How to cite this article
  • SciELO Analytics
  • Curriculum ScienTI
  • Automatic translation


Related links


Jornal de Pneumologia

Print version ISSN 0102-3586On-line version ISSN 1678-4642

J. Pneumologia vol.29 no.4 São Paulo July/Aug. 2003 



Lung tissue remodeling in the acute respiratory distress syndrome*



Alba Barros de SouzaI; Flavia Brandão dos SantosII; Elnara Marcia NegriIII; Walter Araujo ZinIV; Patricia Rieken Macedo RoccoV

IPost-graduate student- Doctorate level – Phisiology - IBCCF-UFRJ
IIPost-graduate student- Masters level - Phisiology/IBCCF-UFRJ
IIIResearcher at LIM59/FM-USP. Specialist Degree in Pneumology by the Sociedade Brasileira de Pneumologia e Tisiologia(Brazilian Society of Pneumology and Tisiology)
IVFull Professor/IBCCF-UFRJ
VAssociate Professor/IBCCF-UFRJ.





Acute respiratory distress syndrome (ARDS) is characterized by diffuse alveolar damage, and evolves progressively with three phases: exsudative, fibroproliferative, and fibrotic. In the exudative phase, there are interstitial and alveolar edemas with hyaline membrane. The fibropro­liferative phase is characterized by exudate organization and fibroelastogenesis. There is proliferation of type II pneumocytes to cover the damaged epithelial surface, followed by differentiation into type I pneumocytes. The fibroproliferative phase starts early, and its severity is related to the patient’s prognosis. The alterations observed in the phenotype of the pulmonary parenchyma cells steer the tissue remodeling towards either progressive fibrosis or the restoration of normal alveolar architecture. The fibrotic phase is characterized by abnormal and excessive deposition of extracellular matrix proteins, mainly collagen. The dynamic control of collagen deposition and degradation is regulated by metalloproteinases and their tissular regulators. The deposition of proteoglycans in the extracellular matrix of ARDS patients needs better study. The regulation of extracellular matrix remodeling, in normal conditions or in several pulmonary diseases, such as ARDS, results from a complex mechanism that integrate the transcription of elements that destroy the matrix protein and produce activation/inhibition of several cellular types of lung tissue. This review article will analyze the ECM organization in ARDS, the different pulmonary parenchyma remodeling mechanisms, and the role of cytokines in the regulation of the different matrix components during the remodeling process.



ARDS – Adult Respiratory Syndrome Discomfort
DAL – Diffuse alveolar lesion
PaO2- Partial arterial oxygen pressure
ALI – Acute lung injury
PI e PII – Pneumocytes  I and  II
TGF – Trasnforming growth factor
ECM –Extracellular matrix
BALF – Bronchoalveolar lavage fluid
PDGF – Platelet derived growth factor
FGF – Growth factors’ family
IL – Interleucin
MMP – Metalloproteinase
TNF – Tissue necrosis factor
EGF – Epidermal growth factor
TIMP – Tissular inhibitor of metalloproteinase
uPA – urokinase plasminogen activator
LPS – Lipopolyssacaride
C5a – Complement  C5a fragment
G-CSF – Granulocyte- colony stimulating factor
GM-CSF – Granulocyte-Macrophage - colony stimulating factor
INF – Interferon
LTB – Leucotrien
PGE2 – Prostaglandin E2
COX-2 – Ciclo-oxygenasis-2
KGF – Keratinocyte Growth Factor
HGF – Hepatocyte growth factor
NF-kB – Nuclear transcription factor- kB
IkBa – Inhibitory Protein for the nuclear transcription factor kB
GC – Glucocorticoids
GR-a – Glucocorticoids cytoplasmic receptors
GRE – Glucocorticoids responsive elements
HSP – Heat shock protein



Acute respiratory distress syndrome (ARDS) is a disease of multifactorial etiology, caused by direct or indirect injury to the lungs. (1,2) It is characterized by diffuse alveolar lesion (DAL), observed as an acute and diffuse lesion of the endothelial and epithelial coatings of the terminal respiratory units and as an increase in the permeability of alveolar-capillary membrane, with plasma exudation to the alveolus’ interior with subsequent pulmonary edema which is not due to an increase in hydrostatic pressure.(3,4)

The pathogenesis of acute lung injury, as well as the adequate treatment of ARDS, has been extensively investigated, but despite that, the mortality of ARDS patients remains high in intensive care units. (4-8) Several predisposing factors have been associated to the development of ARDS, and the main causes of death are pulmonary fibrosis and sepsis secondary to nosocomial pneumonia. (9)

Clinically, there is a considerable heterogeneity among patients. Some of them recover from the severe pulmonary edema within the first seven days, without progressing to the subacute or chronic phases. On the other hand, there are patients who progress to a subacute phase, which develops between five to seven days after the beginning of ARDS onset. This phase is characterized by an increase in alveolar dead space, necessitating a high volume-minute to reach normal or close to normal PaO2 , a decrease in pulmonary system static complacence and an increase in pulmonary shunt, leading to a consequent hypoxemia, refractory   to oxygen administration and also, diffuse infiltrates at chest X-ray.  Some patients, in whom respiratory failure persists for up 14 days, gradually evolve to a chronic phase, with low complacence and increase in alveolar dead space. (5,9)

At the Consensus Conference between the North American and European Pneumology and Intensive Care Societies, it was established that the diagnosis of ARDS should be based on the following findings: 1) respiratory insufficiency of acute onset;  2)bilateral pulmonary infiltrates at chest X-ray; 3) PaO2/FiO2 whichever the PEEP; 4) pulmonary capillary pressures <18 mmHg. The milder cases, characterized by PaO2/FiO2 between 200 and 300 should be denominated pulmonary acute injury (Table 1). (4)



PAI, which characterizes ARDS, evolves progressively, after the initial injury, in three phases (acute or exudative, proliferative and fibrotic), which present different clinical, histopathological and radiological manifestations.

The acute, or exudative phase, presents with injury to the alveoli walls, increase in permeability of alveolar-cappilary barrier, destruction of pneumocytes types I and II (PI and PII) and pulmonary surfactant denaturation, followed subsequently by alveolar edema. (2) Mediators, liberated by circulating inflammatory cells, cause direct injury to the pulmonary microcirculation. (11) Bleeding at the parenchyma surface and dilated alveolar ducts, contrasting with congested, swollen and collapsed alveoli are observed. Also, capillary congestion, interstitial edema and intra-alveolar bleeding occur. The eosinophilic hyaline membranes are more prominent along the alveolar ducts and are made of condensed plasmatic proteins, which, after injury to the alveolar-capillary barrier, pass to the alveolar space and mix themselves with cellular wastes. Immunoglobulins, fibrinogen, surfactant and complement impregnate the hyaline membrane, whereas fibronectin covers minimally the membrane surface. (12,13) (Figure 2).





The proliferative phase has been described as initiating on the third day and lasting for seven or more days, while the intra-alveolar and interstitial exudate organizing phase starts at the acute phase. (14) PII multiply themselves along the alveolar septa to cover previously naked areas of the basal membrane. Fibroblasts and miofibroblasts proliferate at the alveolar walls, migrate through membrane gaps and convert the intra-alveolar exudate into granulation tissue. Posteriorly, there is collagen deposition, with the formation of a fibrous and dense tissue that causes septum thickening. There is a gradual increase in interstitial tissue as ARDS evolves along time.(11) Besides, some recently formed collagen fibrils in the alveolar spaces associated to miofibroblasts were detected. (12) Many patients may have a resolution of ARDS at this phase, but some, progress to pulmonary repair, and may reach the fibrotic phase. (14)

At the fibrotic phase, it is observed fibrotic and obliterated alveoli, irregularities of the alveolar wall thickness associated to dilation and narrowing of air spaces, besides a stratified and squamous cuboidal epithelium. The intra-alveolar exudate organizes itself, with deposition of fibrinogen on hyaline membrane areas, fibronectin on intra-alveolar fibrosis area and keratin on alveolar epithelium, bronchial glands and mesothelium.(12) The exudate organization and alveolar collapse are the main mechanisms responsible for alveolar architecture remodeling and fibrosis development after ALI.(9)

The fibrotic process seems to result from a complex interaction between fibroblasts and macrophages. The fibroblasts migrate to the injured areas and are stimulated to secrete collagen and other matrix proteins. These cells also release several proteases, which are capable of degrading and remodeling those proteins. The stimuli that activates fibroblasts to remodel the lungs may include blood constituents such as fibrin, products of matrix degradation and mediators , such as TGF-b (transforming growth factor-b), which are released by macrophages and cells of the lung parenchyma. (15)

Intra-alveolar fibrosis is more important than interstitial fibrosis in remodeling pulmonary structure, because it results in alveolar obliteration, alveolar walls coalescence and loss of functional alveolar-capillary units. (12)

It is important to point out that these three phases do not behave exactly as described and that not every patient will develop fibrosis. These steps may overlap and, for the same individual, occur in a heterogenous way regarding time and space (different lung regions)(16) Besides, some authors recently described the fibroproliferative phase as a precocious reaction to lung injury. (17 – 20) Thus, inflammatory and repair mechanisms initiate in parallel and not in a serial way. (21)

In this review, we will analyze extra cellular matrix organization in ARDS, the different mechanisms of pulmonary parenchyma remodeling as well as cytokines’s role in the regulation of the different matrix components during the remodeling process.


Extracellular matrix organization in ards

In the normal lung, extracellular matrix proteins (ECM) are secreted locally by matrix cells, more evidently by fibroblasts, and organized in a net throughout spaces surrounding the cells. However, the matrix occupies a significant tissue volume (22) and does not represent an inert mass whose sole function is to provide structural support. It also has information that guides cell migration, binding, differentiation and organization, modulating thus, several processes. So, each cell’s morphology is a reflex of ECM composition since a series of “information” can be transmitted to the cytoskeleton through specific interactions with cell surface receptors. In many acute and chronic interstitial diseases, there are irreversible changes in pulmonary histoarchitecture, which have been receiving a lot of attention in medical literature. The destructive effects of inflammatory cells on the ECM seem to be the main responsible factor for those injuries, releasing not only proteolytic enzymes but also, oxidative agents to the interstitial space. Among the proteases, elastasis, colagenasis and plasminogen activators are particularly important to the ECM’s degradation processes. (23-28)

Three groups of macromolecules are physically associated to form the extracellular matrix:

1) fibrous structural proteins, like collagen and elastic fibers

2) glucoproteins, including fibronectin and laminin

3) proteoglicans

These macromolecules are organized into 2 portions in the tissue: interstitial matrix and basal membrane. (23)

Collagenous fibers

Collagenous fibers are the main components of ECM. Despite their great diversity in the conjunctive tissue, the main ones are types I, II, III, which are fibrillar or interstitial or types IV, V, VI, which are non fibrillar or amorphous. Collagen I is the main structural protein of pulmonary interstitium and is produced in great amounts during lung development and fibrotic reactions. (25)

Collagen turnover in the lungs is a dynamic process, necessary to the maintenance of their normal architecture. (18)

In mild injuries, collagen production is limited, and pulmonary architecture is restored. When the injury involves pleura, bronchi and parenchyma, the repair may result in a focal scar. After a severe injury, the scar may generalize and result in extensive destruction of pulmonary architecture and function, indicating that the biomechanical process implicated on collagen synthesis is capable of reacting very quickly to aggression. (18-20)

Fibrinogenesis occur very early in the course of the lesion and the finding of high levels of pro-collagens I and II in the plasma and in BALF (bronchoalveolar lavage fluid) on the first day of ARDS indicate that collagen synthesis is a precocious event in the response to injury. (26-29)

Armstrong et al, showed increase in the levels of pro-collagen I and decrease in the degradation collagen markers in the BALF of patients under mechanical ventilation for 48 hours, suggesting that an imbalance between collagen synthesis and degradation in ARDS favors collagen I deposition in the early stages of the disease. (18)

Marshal et al. (19) and Chestnut et al. (20) demonstrated important mitogenic activity and increase in pro-collagen III levels in the BALF of patients 24 hours after ARDS diagnosis, reinforcing the hypothesis that fibroblasts proliferation and collagen synthesis are rapidly regulated, indicating that the fibroproliferative process can be established soon after the onset of the disease.

The substitution of collagen type III for collagen type I, which is more rigid, can be responsible for problems in gas exchange and physiological changes that occur at the later stages of fibrosis (30) (Figure 3).



Collagens I and II are synthetized as pro-collagens, which possess pro-peptides in both of their a-chain terminations. Recently formed pro-collagens are secreted by fibroblasts and other mesenchymal cells after the cleavage of the aminoterminal and carboxiterminal a-chain peptides by a specific endopeptidase, forming collagen molecules as well as N-terminal and C-terminal pro-peptides. Increased levels of aminoterminal pro-peptides in the plasma reflect collagen synthesis at the site of the disease and can be used as repairing process markers. (31)

The amount of deposited collagen depends on the extension of cell injury, the intensity of fibroblasts’ proliferation and effector substances present in inflammation, besides vascular hypoperfusion and PaO2 changes which occur during pulmonary injury. TGF-b and insulin related peptides can induce an increase in collagen production by fibroblasts and smooth muscle cells, and also inhibit indirectly collagenase’s production and activity. (32)

As the repair progresses, fibroblasts sinthetize and deposit increased amounts of ECM. Collagen synhthesis is intensified by several factors, including growth factors [platelet derived growth factor (PDGF), families of growth factor (FGF), TGF-b and cytokines (interleucins 1 and 4, IL-1 and IL-4)], which are secreted by leucocytes and fibroblasts. However, the final collagen accumulation does not depend only on its synthesis, but also, on its degradation. (23)

Elastic fibers

Elastic fibers, which provide tissue elasticity, are found associated to collagen fibriles. They are synthetized by many types of lung cells, including condroblasts, miofibroblasts and smooth muscle cells. (33)

The elastic system has three components defined according to the increasing amounts of elastin and fibriles orientation: a) oxitalanic fibers, composed by a bundle of microfibriles; b) elauninic fibers, composed by microfibriles and a small amount of elastin; and c) mature elastic fibers, composed by microfibriles and abundant elastin. (17)

At ultra-structural levels, mammal’s mature elastic fibers are formed by a solid central cylinder composed of abundant amorphous and homogenous material (elastin), surrounded by microfibriles (10 to 12 mm in diameter) which, in transversal section, have a tubular profile. During fiber development, there is, initially, only a microfibriles’ bundle, and then, a gradual deposition of elastin amongst the microfibriles is observed, until complete maturation.

The elastic fibers’ properties depend on their amorphous component. Ontogenesis seems to repeat philogenesis, that is, in the pulmonary reparation processes , after the destruction of elastic system’s mature fibers, there is a gradual substitution for more imature fibers, which are poor in elastin (oxitalanic) and so, less extensible.

Oxitalanic fibers do not elongate under mechanical stress, and prevent excessive tissue stretching, whereas the elauninic fibers present intermediate elastic properties which are between mature elastic fibers and oxitalanic fibers.

Elastin is extremely stable and resistant to proteases’ action. Elastin renovation, which is necessary for tissue growth and remodeling, is very slow, and needs specific enzymes to initiate its degradation, in a way that, under normal conditions, there is little remodeling in adult life. (34)

Like the collagenous fibers, elastic fibers are also reorganized during EMC remodeling.

Studies on animal moderate ARDS models showed a larger deposition of elastic fibers during the repair process 24 hours after the onset of the injury due to the greater deposition of oxitalanic fibers. (17) A two-fold increase of RNAm’ s(messenger ribonucleic acid) expression for elastin is observed three weeks after bleomicin induced injury in hamsters. Thus, it is believed that the process of fibroelastosis – and no only fibrosis – starts early in ARDS evolution (Figure 3).

Fibroelastosis may result from the repair and remodeling subsequent to septal inflammation and elastic fibers fragmentation. Besides that, this process may be partially responsible for the loss of normal architecture of alveolar walls, contributing to the tendency to collapse and to the decrease of the inflammation resolution mechanism. The elastin synthesis’s reactivation is observed in response to intense destruction of the elastic system, but in a disorganized manner, with deleterious consequences to the pulmonary mechanical properties. (36)

Adhesive glicoproteins and integrins

Besides fibrous structural proteins, adhesive glicoproteins and integrins, which are structurally diverse proteins, whose main property is to bind to other EMC components, on one hand and to specific proteins of the cell membrane, on the other, are also present.The main adhesive proteins are fibronectin and laminin. (23,37)

Fibronectin is an adhesive protein, produced by fibroblasts, monocytes, and endothelial and other cells. Its main function is to bind to several EMC components, including collagen, fibrin and proteoglicans, as well as to cells. It is believed that fibronectin is directly involved in cell fixation, dissemination and migration. It is also important to potentialize the sensitivity to other cells to the proliferative effects of the growth factors.

Laminin is the most abundant glicoprotein at the basal membranes and it crosses the basal lamina, binding to specific cell surface receptors and to other EMC components, such as collagen IV and sulphate-heparan. Besides, it is believed that the lamina acts as mediator for the cell binding to connective tissue substrata.

Integrins constitute the main receptor family at the cell surface responsible to fixate the cell to the EMC. Due to its role in adhesion, they are the key components of leucocyte extravasation, platelet aggregation, development and wound healing processes. Some cells require adhesion for their proliferation, and the lack of fixation to EMC elements, through integrins, leads to apoptosis. (23)


Proteoglican mollecules form, in the connective tissue, a gelatinous and hydrated substance, where fibrous proteins are found. They are composed of a central protein bound to one or more polyssacarides, denominated glicosaminoglicans. (38) Some of the commonest include sulphate-heparan, sulphate-condroitin and sulphate-dermatan.

Proteoglicans can also be membrane integrating proteins and thus, cell growth and differentiation modulators. Sindecan, for instance, binds to collagen, to fibronectin and to thrombospondin in the EMC and can modulate growth factors’ activity.

Hyaluronic acid is found in the EMC of several cells and acts as a ligand for central proteins, constituting the structure for big proteoglican complexes. Besides that, it associated to cell surface receptors, which regulate cell proliferation and migration. Also, it binds to a great amount of water, forming a hydrated and viscous gel. It is found in the matrix of cells which are migrating and proliferating, inhibiting cell adhesion and facilitating cell migration. (23)

Therefore, proteoglicans provide mechanical support to tissues, allowing hydrosoluble molecules diffusion and cell migration. They are also important to chemical signaling between cells, binding to signaling molecules, increasing or inhibiting their activity. Besides that, they influence collagenous fibers formation and interact with several cytokines and growth factors. (39) They are frequently found bound to collagenous fibers, elastic fibers and fibronectin in the tissues, participating in EMC organization. (24) In fibroproliferative ARDS and pulmonary idiopatic fibrosis, there is an increase in the biglican, lumican and versican proteoglicans depostion on the septal interstitium. (40)

Versican and lumican are abundant in ARDS and may contribute to the formation of spaces in EMC which are necessary to cell migration, and its participation may be important to the repair process.

Decorin is a small interstitial proteoglican, found in association to collagenous fibrils in the lung. It inhibits fibronectin deposition on EMC, through inhibition o TGF-b activity and limitation of matrix synthesis. Biglican can also act in the same way.

Proteoglican effects and their presence in lung tissue remodeling suggest that they can influence the repair process very early, through their effects on miofibroblasts’ function.(41)


Metaloproteinases (MMP) play an important role in EMC remodeling. These enzymes constitute a family of 11 or more zync-dependent endopeptidases, which are expressed in low levels in normal adult tissues, but in elevated levels during embryonic development, tissue repairing, inflammation, tumoral invasion and metastasis. Growth factors and cytokines can induce [IL-1, TNF-a, TNF-b, TGF-a, epidermal growth factor (EGF), FGF and PDGF] or inhibit (TGF-b and IL-4) metaloproteinases’ gene trasncription. (25) Once formed, activated MMPs are rapidly inhibited by a tissue inhibitor’s family specific to metaloproteinases (TIMP), which are produced by most of mesenchymal cells, preventing thus, these proteinases’ uncontrolled action. (23)

Turnover and EMC remodeling involve MMPs. They are important in the removal o excess proteins, but they can also destroy the lungs’ normal architecture. (32)

Colagenases are part of a MMP’s family, which cleave collagens I, II and III in a specific site. The resulting fragments are more susceptible to digestion by gelatinases (MMP-2 and MMP-9) facilitating their removal from the tissue. (17, 42)

Gelatinase A (or MMP-2) and gelatinase B (or MMP-9) degrade collagen 4, fibronectin and elastin. MMP-2 is distributed through lung parenchyma, whereas MMP-9 is found in free intra-alveolar macrophages and alveolar epithelial cells. (39)

Stromelysins and matrilysins degrade proteoglicans molecules, fibronectin and laminin. Membrane metaloproteinases degrade several cell surface proteins and elastase degrades elastin and fibronectin. (43)

Therapies with MMP inhibitors were recently correlated to histological and physiological lung integrity, suggesting that an increase in protease activity in the EMC has an important role in the development of lung injury associated to ARDS. (44)


Remodeling mechanisms

To fibroproliferate means inducing a stereotyped restoring action to tissue injury, characterized by the substitution of injured epithelial cells by miofiboblasts and its connective tissue’s products in the air spaces, interstitium, respiratory bronchioli and intra-acinar microcirculatory walls. (10,45)

Fibroproliferative response starts almost immediately after the beginning of the injury, in an attempt to repair the damage to the alveolar-capillary membrane. The build-up of inflammatory cells and the passage of plasma to alveolar spaces alter the alveolar microenvironment, leading the tissue remodeling process to progressive fibrosis or to normal alveolar architecture’s restoration. (46)

The repairing process must begin with edema reversal and removal of soluble and insoluble proteins which accumulate in the interstitial and alveolar spaces. This process also involves a very early re-epithelization of alveolar-capillary barrier, with PII proliferation and capillary neoformation (angiogenesis). At the same time, there happens fibroblasts’ proliferation associated to excessive deposition of EMC, which contributes to a decrease in lung complacency and loss of normal alveolar architecture. This fibrotic alveolitis requires more lung remodeling, with gradual pulmonary fibrosis resolution and alveolar-capillary units restoration.(5)

 Alveolar exudates, containing fibrin fragments, fibronectin and other matrix components, form a tri-dimensional scar which maintains alveolar architecture and prevents immediate adhesion of exposed basal membranes. This tri-dimensional matrix provides also, a means to inflammatory, epithelial, mesenchymal and endothelial cell migration. (46)

An important factor is the existence of an intact epithelial barrier, because the injured lung repair involves complex interactions between endothelial and epithelial cells, fibroblasts, alveolar macrophages, coagulation factors, cytokines and growth factors. Besides, intact PII are necessary to the normal surfactant products and the mechanism involved in the removal of alveolar fluid depends on the active sodium transportation, which also requires an intact epithelial barrier. (5) When alveolar epithelium integrity and function are preserved, the removal of alveolar fluid can be stimulated even in the presence of interstitial edema. (47, 48)

The type of endothelial cell that recovers alveolar surface depends, in part, on the injury extension. PII proliferate and differentiate in PI in lung areas where there is less injury, whereas epithelial bronchial cells recover areas where no PII survives. The normal alveolar space has fibrinolytic activity, due to the presence of urokinase type plasminogen (uPA), so that the alveolar space eliminates efficiently its intra-alveolar fibrine. In ARDS patients, there is fibrin build-up in the alveolar interior, which occurs, partly, because of this fibrinolytic activity suppression. Epithelial cells influence the fibrinolytic balance inside the air spaces through urokinase synthesis and the plasminogen activator inhibitor. Thus, the persistence of fibrine in fibrotic lung diseases can be, in part, due to loss of epithelial cells or to alterations in their fibrinolytic functions.

An influx of coagulation factors to the alveolar spaces also contributes to the build up of intra-alveolar fibrin. During acute lung injury, the alveolar pro-clothing activity increases by the same proportion as fibrin deposition.

Intra-alveolar fibrin removal is important for disease resolution. If extra-vascular fibrin is removed, it is possible to reconstitute normal alveolar space. If fibrin remains, fibroblasts migrate to the fibrin matrix and secrete interstitial collagen. Fibrotic scars, thick alveolar walls and obliterated air spaces will be formed, depending on the site and extension of residual exudate. (46)

It is believed that apoptosis plays and important role in the regulation of several biological processes, including inflammatory response. The neutrophils that migrate to an area of inflammation are removed by necrosis, liberating toxic mediators, or by apoptosis, which involves individual cells involution, causing little tissue damage. (16) Apoptotic neutrophils are rapidly ingested by macrophages, before membrane integrity is lost. In this manner, apoptosis provides a way to remove, with minimal tissue damage, neutrophils from a given site.

Apoptosis inhibition results in an increased number of viable neutrophils, which prolong neutrophilic alveolitis, or in an increase in necrosis, which contributes to ALI. Several inflammatory mediators inhibit apoptosis and prolong neutrophil survival in vitro. These include lipopolissacaride (LPS), C5a complement fragment (C5a), granulocyte-macrophage colony stimulator factor (G-CSF, GM-CSF), interferon (INF-a, IL-2, IL-6 and leucotrien (LTB4). Some of these mediators were found in the BALF of ARDS patients, suggesting that neutrophil apoptosis is inhibited during in vivo inflammation. (49)

In late lung injury, apoptosis also plays an important role in the repair process, eliminating granulation tissue and excess neutrophils, and is fundamental for the removal of the intra-alveolar fibrosis component, besides removing excessive numbers of PII from alveolar epithelium.(46)


Cytokines and remodeling in ards

When TNF-a and IL-1b are liberated in the lungs, they act on epithelial and endothelial cells, fibroblasts, platelets, EMC and surrounding recruited cells (neutrophils and limphocytes), causing secondary cytokine liberation waves, amplifying thus the inflammation. (50)

IL-1b is the most important cytokine found in BALF at the early phase of ARDS. It plays and important local role, but it also presents a small effect on sites which are far from the acute inflammation. Such fact may indicate that there are, in the plasma, strong regulating mechanisms, blocking the circulating cytokines effects. The presence of increased levels of TNF-a and IL-1b receptors, in similar concentrations in the edema and in the plasma, indicate that there is a pro-inflammatory cytokine neutralization, both in the alveolus as in the circulation.

It seems that the alveolar imbalance between pro and anti-inflammatory cytokines is partly responsible for the acute inflammation seen in ARDS, (31,51) so that the inflammatory balance is more important, clinically and physiologically, than each individual cytokine’s concentration. (26)

TNF-a, an important inflammatory mediator, activates leucotriens and prostaglandin-E synthesis (PGE2), stimulating leucocyte infiltration in the lungs. Besides, is has inhibitory effects on surfactant metabolism, decreasing phospholipids amounts. This effect occurs through the stimulation of the enzymes involved in surfactant’s lipid synthesis. (27,28)

TNF-a and IL-1b are important inducers of IL-8 liberation by several cells, including alveolar macrophages, endothelial and epithelial cells and fibroblasts. (31) IL-8 is a chemotactic factor for neutrophils, eosinophils, monocytes and limphocytes and it has been proposed that IL-8 is the main responsible for neutrophil influx to the lungs. Neutrophils are important inflammatory cells in ARDS, but are not the only ones necessary or sufficient for the development of the process. However, they act as lung inflammation markers. (29) Additionally, IL-8 presents angiogenic activity, induces collagen synthesis and cell proliferation. (15)

IL-6 is a potent inducer of the metalloproteinase inhibitor (TIMP). Increased levels of this cytokine may have a significant role in the development of lung fibrosis, through the non regulation of TIMPs, which could inhibit normal remodeling and removal of EMC’s excess proteins. (10)

PGE2 decreases fibroblasts proliferation and reduces collagen levels inhibiting their synthesis and promoting their degradation. Pulmonary fibroblasts, isolated from patients with idiopathic pulmonary fibrosis, have a decreased capacity of PGE2 synthesis and of expressing cicloxigenase -2 (COX2). In the absence of COX-2, the fibroblasts are incapable of increasing their capacity to synthetize PGE2 and, consequently, they are incapable of limiting their proliferation, collagen synthesis and inflammatory mediators’ production. (46)

Several cytokines and growth factor play an important role in inflammation persistence and in the determination of the occurrence (or not) of fibrosis. Transforming growth factors (TGF) are complex cytokines with multiple effects on mesenchymal and epithelial cells. They can be produced by macrophages, epithelial or mesenchymal cells and act through autocrine and paracrine pathways. TGF-a can promote epithelial or mesenchymal cells’ proliferation and act through collagen production by fibroblasts, whereas TGF-b inhibits epithelial cells replication and incresases fibronectin production. (13)

Alveolar macrophages are the predominant cells in the alveolar space. Apart from their defense function against inhaled substances and microorganisms, there are evidences suggesting that these cells may have a role in lung inflammation and fibrosis, increasing in numbers and regulating cytokines, such as IL-1, PDGF, TNF-a, TGF-b and proteins, such as fibronectin.

Of the cytokines produced by alveolar macrophages, TGF-b is one of the most potent regulators of inflammation and synthesis of connective tissue in vitro and in vivo. Besides, it is a potent chemoatractor for fibroblast, inducing it to synthetize collagen and other EMC proteins. (52)

Keratinocyte growth factor (KGF), hepatocyte growth factor (HGF) and GM-GSF are mitogenic for PII, and are important for re-epithelization of alveolar surface. GM-CSF can act directly on PII, regulating its proliferation, differentiation or apoptosis, or indirectly, regulating the autocrine pathways which influence PII proliferation or differentiation. (46)

The nuclear transcription factor kB (NF - kB) is a transcription factor found in the cytoplasm in an inactive form, which is stabilized by the NF-kB (IkBa) inhibitory protein. When liberated, it translocates to the nucleus and binds to specific gene regions to start the transcription of several inflammatory cytokines. (50) The increased activation of NF-kB in peripheral monocytes of patients in sepsis and in alveolar macrophages of patients with established ARDS, resulting in pro-inflammatory cytokines increase, such as TNF-a, IL-1b, IL-6, IL-8 and intracellular adhesion molecules has been demonstrated.

Figure 4 shows that while most of cytokines are pro-inflammatory, there are also families of anti-inflammatory interleucins. In the lungs, for instance, IL-4, IL-6, IL-10 and IL-13 present potent anti-inflammatory effects, related to the capacity to inhibit TNF-a production. (15)



Glucocorticoid hormones (GC), produced by the adrenal cortex, are the most important inflammation inhibitors, through the activation of their cytoplasmic receptors (GR-a), with GC-GR-a complexes formation. These complexes modulate glucocorticoid transcription in a hormone-dependent way, binding to glucocorticoid responsive elements (GRE) and interfering with transcription factors’ activity, such as NF-kB, acting on the genes regulated by those factors. (53)

Other pathogenic mediators, identified at the ARDS proliferative phase, include advanced glicosilation end products (AGE), 47- heat shock proteins (HSP-47) and activin A. AGE binds to macrophages’ receptor sites and stimulate them to liberate cytokines which act on fibrosis, HSP-47 is involved in intracellular processing of collagen molecules. Activin A stimulates fibroblast proliferation and participates in induction and differentiation processes in early embryogenesis. (21)



Remodeling regulation of EMC, under normal conditions and in several pulmonary diseases, such as ARDS, results in a complex integrative mechanism, which transcripts elements that degrade matrix proteins and produce activation/inhibition of several lung tissue cell types. (54) Some of the growth factors which stimulate the synthesis of connective tissue molecules also modulate enzyme degradation and activation, whose actions consist in remodeling the connective tissue architecture. (23)

In ARDS, epithelial and endothelial injuries start an event sequence, such as inflammatory cells influx, which liberates cytokines, activating fibroblasts and enhancing MMPs and TIMPs synthesis and activity. (26,54)

Nevertheless, several questions on how EMC remodeling behaves are not yet well understood and are still the object of research.



1. Meduri GU, Chrousos GP. Duration of glucocorticoid treatment and outcome in sepsis: is the right drug used the wrong way? Chest 1998; 114:355-60.        [ Links ]

2. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-48.        [ Links ]

3. McIntyre RC Jr, Pulido EJ, Bensard DD, Shames BD. Thirty years of clinical trials in acute respiratory distress syndrome. Crit Care Med 2000;28:3314-31.        [ Links ]

4. Bernard GR, Artigas A, Bringham KL, Carlet J, Falke K, Hudson M, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818-24.        [ Links ]

5. Artigas A, Bernard GR, Carlet J, Dreyfuss D, Gattinoni L, Hudson L, et al. The American-European Consensus Conference on ARDS, Part 2. Am J Respir Crit Care Med 1998;157:1332-47.        [ Links ]

6. Artigas AJ, Carlet J, Le Call JR, Chastang C, Blanch L, Fernández R. Clinical presentation, prognostic factors and outcome of ARDS in the European Collaborative Study (1985-1987): a preliminary report. In: Zapol WM, Lemaire F, eds. Adult respiratory distress syndrome. New York: Marcel Dekker, 1991;37-64.        [ Links ]

7. Milbergh JA, Daris DR, Steinberg KP, Hudson LD. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993. JAMA 1995;306-9.        [ Links ]

8. Wheeler AP, Bernard GR, Rinaldo JE. Future clinical trials of pharmacological therapy of adult respiratory distress syndrome. In: Artigas A, Lemaire F, Suter PM, Zapol WM, eds. Adult respiratory distress syndrome. London: Churchill Livingstone, 1991;499-507.        [ Links ]

9. Meduri GU, Belenchia JM, Estes RJ, Wunderink RG, Torky ME, Lee­per KV Jr. Fibroproliferative phase of ARDS – Clinical findings and effects of corticosteroids. Chest 1991;100:943-52.        [ Links ]

10. Meduri GU. The role of the host defense response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment. Eur Respir J 1996;9:2650-70.        [ Links ]

11. Wallace WAH, Donnelly SC. Pathogenesis of acute microvascular lung injury and the acute respiratory distress syndrome. Eur Respir Monogr 2002;7:22-32.        [ Links ]

12. Fukuda Y, Ishizaki M, Masuda Y, Kawanami O, Masugi Y. The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage. Am J Pathol 1987;126:171-82.        [ Links ]

13. Schwarz MA. Acute lung injury: cellular mechanisms and derangements. Paediatr Respir Rev 2001;2:3-9.        [ Links ]

14. Fein AM, Calalang-Colucci MG. Sepsis and septic shock. Acute lung injury and acute respiratory distress syndrome in sepsis and septic shock. Crit Care Clin 2000;16:289-317.        [ Links ]

15. Ward PA, Hunninghake GW. Lung inflammation and fibrosis. Am J Respir Crit Care Med 1998;157:S123-9.        [ Links ]

16. Ingbar DH. Mechanisms of repair and remodeling following acute lung injury. Clin Chest Med 2000;21:589-616.        [ Links ]

17. Rocco PRM, Negri EM, Kurtz PM, Vasconcellos FP, Silva GH, Capelozzi VL, et al. Lung tissue mechanics and extracellular matrix remodeling in acute lung injury. Am J Respir Crit Care Med 2001;164:1067-71.        [ Links ]

18. Armstrong L, Thickett DR, Mansell JP, Ionescu M, Hoyle E, Billinghurst RC, et al. Changes in collagen turnover in early acute respiratory distress syndrome. Am J Respir Crit Care Med 1999;160:1910-5.        [ Links ]

19. Marshall RP, Bellingan G, Webb S, Puddicombe A, Goldsack N, McAnulty RJ,et al. Fibroproliferation occurs early in the acute respiratory distress syndrome and impacts on outcome. Am J Respir Crit Care Med 2000;162:1783-8.        [ Links ]

20. Chesnutt AN, Matthay MA, Tibayan FA, Clark JG. Early detection of type III procollagen peptide in acute lung injury. Pathogenetic and prognostic significance. Am J Respir Crit Care Med 1997;156:840-5.        [ Links ]

21. Tomashefski JF Jr. Acute respiratory distress syndrome. Pulmonary pathology of acute respiratory distress syndrome. Clin Chest Med 2000; 21:435-66.        [ Links ]

22. Raghow R. The role of extracellular matrix in postinflammatory wound healing and fibrosis. FASEB J 1994;8:823-31.        [ Links ]

23. Cotran RS, Kumar V, Collins T, Robbins SL. Pathology basis of disease. 6th ed. Philadelphia: W.B. Saunders, 1999;89-112.        [ Links ]

24. Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson J. The cell. 3ª ed. São Paulo: Ed. Artes Médicas Sul, 1994;950-1010.        [ Links ]

25. Goldstein RH. Control of type I collagen formation in the lung. Am J Physiol 1991;5:L29-40.        [ Links ]

26. Park WY, Goodman RB, Steinberg KP, Ruzinski JT, Radella II F, Park DR. Cytokine balances in the lung of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;164:1896-903.        [ Links ]

27. Chen CM, Fang CL, Chang CH. Surfactant and corticosteroid effects on lung function in a rat model of acute lung injury. Crit Care Med 2001;29:2169-75.        [ Links ]

28. Tasaka S, Hasegawa N, Ishizaka A. Pharmacology of acute lung injury. Pulm Pharmacol Ther 2002;15:83-95.        [ Links ]

29. Baughman RP, Gunther KL, Rashkin MC, Keeton DA, Pattishall EN. Changes in the inflammatory response of lung during acute respiratory distress syndrome: prognostic indicators. Am J Respir Crit Care Med 1996;154:76-81.        [ Links ]

30. Entzian P, Hückstädt A, Kreipe H, Barth J. Determination of serum concentrations of type III procollagen peptide in mechanically ventilated patients. Am Rev Respir Dis 1990;142:1079-82.        [ Links ]

31. Pugin J, Verghese G, Widmar MC, Matthay MA. The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. Crit Care Med 1999; 27:304-15.        [ Links ]

32. Meduri GU. Levels of evidence for the pharmacologic effectiveness of prolonged methylprednisolone treatment in unresolving ARDS. Chest 1999;116:116-8.        [ Links ]

33. Starcher BC. Lung elastin and matrix. Chest 2000;117:229-34.        [ Links ]

34. Montes GS. Distribution of oxytalan, elaunin and elastic fibres in tissues. J Braz Assoc Adv Sci 1992;44:224-33.        [ Links ]

35. Raghow R, Lurie S, Sayer JM, Kang AH. Profiles of steady state levels of messenger RNAs coding for type I procollagen, elastin, and fibronectin in hamster lungs undergoing bleomycin-induced interstitial pulmonary fibrosis. J Clin Invest 1985:76:1733-9.        [ Links ]

36. Negri EM, Montes GS, Saldiva PH, Capelozzi VL. Architectural remodelling in acute and chronic interstitial lung disease: fibrosis or fibroelastosis? Histopathology 2000;37:393-401.        [ Links ]

37. Snyder LS, Hertz MI, Harmon KR, Bitterman PB. Failure of lung repair following acute lung injury – Regulation of the fibroproliferative response (part 1). Chest 1990;98:733-8.        [ Links ]

38. Ebihara T, Venkatesan N, Tanaka R, Ludwig MS. Changes in extracellular matrix and tissue viscoelasticity in bleomycin-induced lung fibrosis. Temporal aspects. Am J Respir Crit Care Med 2000;162:1569-76.        [ Links ]

39. Miserocchi G, Negrini D, Passi A, De Luca G. Development of lung edema: interstitial fluid dynamics and molecular structure. News Physiol Sci 2001;16:66-71.        [ Links ]

40. Costa MLG. Remodelamento pulmonar na síndrome da angústia respiratória aguda (SARA) e na fibrose pulmonar idiopática (FPI): caracterização dos proteoglicanos (PG) biglican, lumican e versican [tese]. São Paulo: Faculdade de Medicina, Universidade de São Paulo, 2002;39-40.        [ Links ]

41. Bensadoun ES, Burke AK, Hogg JC, Roberts CR. Proteoglycan deposition in pulmonary fibrosis. Am J Respir Crit Care Med 1996;154: 1819-27.        [ Links ]

42. Corbel M, Boichot E, Lagent V. Role of gelatinases MMP-2 and MMP-9 in tissue remodeling following acute lung injury. Braz J Med Biol Res 2000;33:749-54.        [ Links ]

43. Pardo A, Selman M. Matrix metalloproteinases and lung injury. Braz J Med Biol Res 1996;29:1109-15.        [ Links ]

44. Carney DE, McCann UG, Schiller HJ, Gatto LA, Steinberg J, Picone AL, et al. Metalloproteinases inhibition prevents acute respiratory distress syndrome. J Surg Res 2001;99:245-52.        [ Links ]

45. Bellingan GJ. Resolution of inflammation and repair. Eur Respir Monogr 2002;7:70-82.        [ Links ]

46. Galen B, Toews MD. Cellular alterations in fibroproliferative lung disease. Chest 1999;116:112-6.        [ Links ]

47. Berthiaume Y, Folkesson HG, Matthay MA. Lung edema clearance: 20 years of progress. Invited Review: Alveolar edema fluid clearance in the injured lung. J Appl Physiol 2001;2207-13.        [ Links ]

48. Matthay MA. Alveolar fluid clearance in patients with ARDS. Does it make difference? Chest 2002;340S-43S.        [ Links ]

49. Matute-Bello G, Liles WC, Radella II F, Steinberg KP, Martin TR. Neutrophil apoptosis in the acute respiratory distress syndrome. Am J Respir Crit Care Med 1997;156:1969-77.        [ Links ]

50. Meduri GU. Host defense response and outcome in ARDS. Chest 1997; 112:1154-8.        [ Links ]

51. Keane MP, Strieter RM. The importance of balanced pro-inflammatory and antiinflammatory mechanisms in diffuse lung disease. Respir Res 2002;3:5-11.        [ Links ]

52. Khalil N, Whitman C, Zuo L, Danielpour D, Greenberg A. Regulation of alveolar macrophage growth factor-b secretion by corticosteroids in bleomycin-induced pulmonary inflammation in the rat. J Clin Invest 1993;92:1812-8.        [ Links ]

53. Meduri GU, Tolley EA, Chrousos GP, Stentz F. Prolonged methylprednisolone treatment suppress systemic inflammation in patients with unresolving acute respiratory distress syndrome. Evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids. Am J Respir Crit Care Med 2002;165:983-91.        [ Links ]

54. Swiderski RE, Dencoff, JE, Floerchinger CS, Shapiro SD, Hunninghake GW. Differential expression of extracellular matrix remodeling genes in a murine model of bleomycin-induced pulmonary fibrosis. Am J Pathol 1998;152:821-8.        [ Links ]



Correspondence to
Patricia Rieken Macedo Rocco, M.D., Ph.D
Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho, Ilha do Fundão
21949-900 – Rio de Janeiro, RJ, Brasil
Tel. (+5521) 2562-6557
Fax (+5521) 2280-8193

Received for publication on 22/02/03
Approved after review on 23/04/03



* Study performed at Laboratório de Fisiologia da Respiração, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil; LIM59 (Biologia Celular), Universidade de São Paulo e Departamento de Tórax (Hospital do Câncer AC Camargo), São Paulo, SP, Brasil.

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License