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Physiol Rev 89: 759 –775, 2009;
doi:10.1152/physrev.00019.2007.
Lung Parenchymal Mechanics in Health and Disease
DÉBORA S. FAFFE AND WALTER A. ZIN
Laboratory of Respiration Physiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio
de Janeiro, Rio de Janeiro, Brazil
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Faffe DS, Zin WA. Lung Parenchymal Mechanics in Health and Disease. Physiol Rev 89: 759 –775, 2009;
doi:10.1152/physrev.00019.2007.—The mechanical properties of lung tissue are important determinants of lung
physiological functions. The connective tissue is composed mainly of cells and extracellular matrix, where collagen
and elastic fibers are the main determinants of lung tissue mechanical properties. These fibers have essentially
different elastic properties, form a continuous network along the lungs, and are responsible for passive expiration.
In the last decade, many studies analyzed the relationship between tissue composition, microstructure, and
macrophysiology, showing that the lung physiological behavior reflects both the mechanical properties of tissue
individual components and its complex structural organization. Different lung pathologies such as acute respiratory
distress syndrome, fibrosis, inflammation, and emphysema can affect the extracellular matrix. This review focuses
on the mechanical properties of lung tissue and how the stress-bearing elements of lung parenchyma can influence
its behavior.
I. INTRODUCTION
The mechanical properties of lung tissue are important determinants of the overall mechanical behavior of
the respiratory system, contributing significantly to both
elastic and dissipative (resistive) properties of the lung. In
fact, the dissipative properties of lung tissue are the major
determinants of lung resistance within the breathing frequency range (11, 14, 143). The biomechanical properties
of connective tissues play fundamental roles in the functioning of almost every organ and are critical determinants of how mechanical forces acting on the body/organ
produce physical changes at the cellular level (144). It is
recognized that mechanical interactions between cells
and the extracellular matrix (ECM) have regulatory efwww.prv.org
fects on cellular physiology, leading to reorganization and
remodeling of the ECM, which in turn influences lung
function (19, 144).
The act of breathing entails the cyclic application of
physical stresses at the pleural surface as well as the
transmission of those stresses throughout the lung tissue
and its adherent cells (40). The applied stresses result in
length changes of parenchymal structures (strain), yielding volume variation. To support extreme strain variations, while maintaining the minimal tissue diffusional
barrier necessary for adequate gas exchange, lung parenchyma presents important stress-bearing systems, including the gas-liquid interface, the connective tissue matrix,
and the contractile apparatus (38). These stress-bearing
elements can be significantly changed during pathological
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I. Introduction
II. Tissue Mechanics: Energy Dissipation and Storage During Ventilation
A. Elastance and resistance
B. Viscoelasticity
C. Stress-strain relationship and lung tissue components
D. Stress-bearing elements: mechanical contributions of elastin, collagen, fiber network,
and interstitial cells
E. Mechanical interactions between collagen and proteoglycans
F. Contractile elements and tissue mechanics during induced constriction
III. Tissue Mechanics in Lung Diseases
A. Lung parenchyma remodeling: micromechanics of injured lungs
B. Lung fibrosis
C. Lung inflammation: asthma
D. Emphysema
IV. Conclusion
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DÉBORA S. FAFFE AND WALTER A. ZIN
states, thus affecting lung mechanics. Excellent reviews
can be found on macroscale (90) and microscale (138,
144) lung mechanics, as well as on transmission of mechanical stresses from the pulmonary macroscale to the
cell microenvironment (40). This review focuses on the
mechanical properties of lung tissue and how the stressbearing elements of lung parenchyma can influence its
behavior in normal and pathological conditions.
II. TISSUE MECHANICS: ENERGY DISSIPATION
AND STORAGE DURING VENTILATION
During quiet breathing, energy is used to overcome
elastic and resistive forces. The classic equation of motion describes the relationship among pressure, volume,
and flow as P(t) ⫽ EV(t) ⫹ RV⬘(t) ⫹ P0, where at any
instant t, P is applied pressure, E is elastance, V is volume,
R is resistance, V⬘ is flow, and P0 is pressure corresponding to transpulmonary pressure at end expiration. Thus
resistive pressure (Pres) refers to pressure dissipated to
overcome resistance (R); whenever flow is absent, Pres
equals zero (112). The representative model for this equation is the resistive-elastic model, characterized by a single resistive compartment connected to a single elastic
compartment, and represented by a dashpot in parallel
with a spring. To increase volume in this resistive-elastic
model, part of the applied energy would be dissipated by
the dashpot (resistance), whereas another fraction of the
total energy would be stored in the spring (elastance),
providing the driving pressure for expiration (Fig. 1). The
resistive-elastic model, however, does not explain the
pressure-time profile observed after interruption of a constant flow inflation, where a slow pressure decay can be
found even after flow has ceased (stress relaxation).
It has been consistently observed that recoil pressures at the same lung volumes are always less during
deflation than inflation (hysteresis), meaning that the mechanical energy (work) expended during inflation exceeds that recovered during deflation. With repeated cycling, loops enclose an area representing the energy lost
per cycle (59). During quiet breathing, the area enclosed
by the pressure-volume or stress-strain curves is nearly
independent of frequency. Thus, under constant amplitude cycling, energy dissipation is nearly independent of
frequency (1). However, the dissipation is proportional to
the product of resistance and frequency. Taken together,
these findings imply that resistance must be inversely
proportional to frequency (6, 43). Tissue resistance sharply
contrasts with airway resistance, which exhibits much less
frequency dependence (59).
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FIG. 1. Linear unicompartmental model (resistive-elastic model).
A: anatomical representation: tube with resistance (R) and ballon with
elastance (E). B: mechanical representation characterized by a dashpot
with Newtonian resistance (R) in parallel with a spring with elastance
(E) submitted to the same deformation volume (V).
B. Viscoelasticity
The relationship between stress and strain, e.g., the
constitutive equation, contains information on the underlying mechanisms and structure contributing to such a
behavior (43). Closely related to the hysteresis seen during volume cycling of the lung are the phenomena of
stress adaptation and creep. In this line, soft biological
tissues are known to be highly viscoelastic in nature. In
contrast to perfect elastic materials, viscoelastic substances do not maintain a constant stress under constant
deformation; the stress, instead, slowly relaxes (stress
relaxation). On the other hand, under constant stress, the
material undergoes a continuous deformation in time, i.e.,
creep (15, 23, 97, 142) (Fig. 2). Indeed, viscoelasticity
represents an important component of respiratory mechanics, being responsible, in some cases, for most of the
pressure dissipated during breathing (4, 88, 129). The
viscoelastic model adds a third component to the resistive-elastic one, the Maxwell body, in which a dashpot
(viscous element) lies in series with a spring (elastic
element) (55, 56) (Fig. 3). In this model, the spring can
transfer energy to the dashpot that burns it as heat; hence,
the energy of the system may diminish even when it is not
moving. The slow decay in pressure observed after endinflation occlusion can be perfectly superimposed to alveolar pressure measured by alveolar capsules, thus representing energy dissipation at the lung parenchyma level
(119). The linear viscoelastic model predicts dynamic
elastance and its frequency dependence quite well (26,
142), but it cannot account for about one-third of the
energy loss (hysteresis), suggesting that additional nonviscous plastoelastic elements are required in the model.
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A. Elastance and Resistance
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FIG. 2. Viscoelastic materials, such as soft biological tissues, when
held at a constant deformation (strain) show a progressive decrease in
stress, called stress relaxation (A), and when held at a constant stress
they show a progressive increase in deformation (strain), i.e., creep (B).
They do not impart time and frequency dependence
(stress relaxation and dynamic elastance) but do consume energy (59).
Lung parenchyma displays prominent viscoelastic
behavior. However, resistive pressures across tissue, in
contrast to airways, are non-Newtonian (55, 56). It is
recognized that the major part of energy dissipation associated with cyclic lung expansion depends on the
amount of expansion but not the rate of expansion, demonstrating that lung tissue shows a stress incompatible
with the notion of a viscous stress (41). During cycling,
the stress that develops in the viscoelastic body displays
a component in phase with strain, which is the elastic
stress contributing to the storage modulus (or dynamic
elastance in the lung), and a component out of phase with
strain, corresponding to the viscous dissipation and contributing to the loss modulus (or lung tissue resistance, or
damping) (6, 55). Thus the relative contribution of tissue
resistance to overall lung resistance can be magnified by
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FIG. 3. Viscoelastic model. A: anatomical representation with two
resistive components (R1 and R2) and two elastic components (E1 and
E2). B: mechanical representation characterized by a resistive component (R1) in parallel with a Kelvin body, which consists of an elastic
component (E1), representing the static elastance, in parallel with a
Maxwell body, a dashpot assembled in series with a spring, representing
the viscoelastic behavior. The distance between the two horizontal bars
is analog to lung volume (V), and the tension between them represents
the airway opening pressure (P).
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large volume changes and by low flow rates, the opposite
effect being observed in the airway component (83).
The viscoelastic properties of lung tissue cause the
effective tissue resistance (Rti) to be high at very low
frequencies but then decrease quasi-hyperbolically to
zero at higher frequencies (6, 12, 41, 51, 146). As a consequence, in many species, Rti of the healthy lung represents the main contributor to total lung resistance during
breathing (85). In this line, study using alveolar capsules
disclosed that from 0.5 to 2.0 Hz and in the face of
physiological tidal volumes, lung tissue resistance represents a major component of total pulmonary resistance
(83). At breathing frequencies in the range of 0.2– 0.4 Hz, tissue
resistance can account for ⬃40% of lung resistance (6).
During a physiological tidal excursion, there is little
or no influence of airway inhomogeneities on measurements of lung mechanics in the healthy lung. On the other
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authors also postulated that dissipative and elastic processes are coupled at the level of the stress-bearing element, which represents a structure composed of anatomically distinct materials. Thus a modification in ␩ reflects
either a change in hysteretic behavior within one of those
materials or an alteration in the mechanical interaction
among them (41). However, the structural damping law is
only descriptive; it does not specify the mechanisms
through which the coupling of dissipative and elastic
processes might come about, and thus the molecular basis of
␩ remains obscure (62). Nevertheless, four processes are
implicated in this phenomenon: the kinetics of crossbridge attachment-detachment within the contractile element, the kinetics of the surface-active molecule adsorption-desorption to the surface film, the kinetics of fiberfiber networking within the connective tissue matrix, and
the kinetics of recruitment-derecruitment (41).
C. Stress-Strain Relationship and Lung
Tissue Components
The elastic recoil of the lung at normal breathing
frequencies is dominated by the nonlinear stress-strain
characteristics of the lung tissue (139), whereas the main
stress-bearing constituents are collagen and elastin fibers
(43). In the lung parenchyma elastin provides elasticity,
especially at lower stress levels, while the collagen fibers
are loosely arranged and wavy, not becoming tight until
the parenchyma is distended (43). In other words, elastin
responds for load bearing at low strains; as strain increases, the collagen fibers progressively take up more
load, thereby stiffening the tissue (86). These fibers significantly differ in their mechanical properties: elastin is
highly stretchable before rupturing, while collagen is
much stiffer and significantly less stretchable than elastin.
Indeed, collagen represents the basic structural element
for soft and hard tissues that provides mechanical integrity and strength to a variety of tissues and organs. On the
other hand, elastin is the most “linear” elastic biosolid
material. Both fiber types show a complex organization
and are integrated with cells and intercellular substance
in the tissues. This intercellular substance, called ground
substance, contains proteoglycans, glycosaminoglycans,
and tissue fluid. Depending on how the fibers, cells, and
ground substance are organized into a structure, the mechanical properties of the tissue vary (43). The importance of fiber organization is especially evident for collagen that is organized into many different kinds of structures according to the organ/tissue function, varying from
the simplest parallel fibered structure found in tendon
and ligaments to the most complex structures of blood
vessels (43).
Loading and unloading of animal tissues result in two
different stress-strain curves (hysteresis loop), deviating
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hand, true static lung elastance (EL) is approached at very
low frequencies, and, as frequency increases, EL augments owing to either tissue viscoelasticity (i.e., a real
tissue phenomenon) or airway inhomogeneities (i.e., an
airway phenomenon) (85). In general, although Rti varies
widely with tidal volume, lung volume, and lung size,
tissue hysteresivity (␩) remains remarkably constrained
to a narrow range. Indeed, ␩ exhibits small variability,
frequency invariance, and numerical consistency across
species (41).
Numerous studies have used models mainly in the
context of describing oscillatory behavior of lung tissue
where the hysteresis area of the P-V curve is nearly independent of frequency and the stress relaxation function
follows a power law dependence on time (103, 142, 146).
The constant-phase model by Hantos et al. (52), describing the viscoelastic properties of lung tissues, has been
considered superior to the classic spring and dashpot
representation. Although the electrical analog of viscoelastic processes as well as phenomenological and mechanical approaches yield good quantitative correspondence with data, they lack anatomic and mechanistic
specificities (52).
Later models tried to deal with dynamic tissue behavior on a mechanistic basis (96). Some mechanisms
have been proposed as contributors to the constant-phase
tissue viscoelasticity, such as the structural disposition of
fibers and their instantaneous configuration during motion (the interaction between fibers in close proximity),
since elastic fibers dissipate energy as they slip with
respect to each other (96). Additionally, lung tissue might
exhibit molecular mechanisms similar to those proposed
for polymer rheology (142). Maksym and Bates (86) suggested a role for the relative stress-bearing contributions
of collagen and elastin fibers based on the differential
elastic properties of these two types of fibers, in which
collagen fibers were progressively recruited with strain.
Bates (11) also proposed that the nonlinear elastic properties and linear elastic behavior of lung tissues arise from
different physical processes, whereas elastic recoil is
linked to geometry as fibers rearrange themselves; stress
adaptation would reflect a process of diffusion due to the
thermal motion of the fibers with respect to each other
and to the ground substance (11).
Micromechanical studies have tried to determine tissue microrheological behavior, that is, the measurement
of its complex elastic modulus G. G represents the complex ratio between stress and strain in the frequency
domain and can be split into an elastic component G⬘ and
a viscous or frictional component G⬘⬘. Fredberg and Stamenovic (41) showed that dissipative and elastic processes are coupled in lung tissue, and hysteresivity (␩)
denotes the empirical variable that quantifies the dependence of dissipative processes on elastic processes, a tax
that must be spent any time elastic energy is stored. These
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FIG. 4. Schematic representation of the shear stress mechanism. A
thin-walled elastic tube (airway or blood vessel) is embedded in springnetwork material, whereas pressures P0, P1, and P2 act on the walls of
the tube. P1 is uniform throughout the spring network. In the initial
pretensed state, P1 and P2 are assumed to be equal and greater than P0,
thus rendering uniform the initial state of the material. If the pressures
in the three regions change slightly, a nonuniform deformation can
occur, and the mechanics of the thin-walled tube are affected by the
surrounding material. [Adapted from Wilson (168).]
bance are spread out by the surrounding material if the
shear modulus is low, whereas the effects of the surrounding material on the mechanics of a local element are
greater if the shear modulus is high.
The microscopic properties of the parenchymal network influence both elastic and resistive properties of the
lung. Hysteresis, which can be measured as the area
enclosed by the pressure-volume loop of the lung, closely
relates to tissue resistance (20, 41). Indeed, the potential
sources of hysteresis in the normal lung include the airliquid interface (92, 102, 169), parenchymal contractile cells
(38), and the behavior of the collagen-elastin network (20, 96,
175), that is, the main stress-bearing systems (38).
D. Stress-Bearing Elements: Mechanical
Contributions of Elastin, Collagen, Fiber
Network, and Interstitial Cells
The principal stress-bearing elements of septal tissues have been commonly assumed to be the connective
tissue fibers. Collagen, elastin, proteoglycans, and glycosaminoglycans constitute the major components of the
connective tissue (93, 166). Although the precise contribution of each of these elements remains unknown, the
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from the linear Hooke’s law and disclosing the existence
of an energy dissipation mechanism (43). Furthermore,
when held at constant strain, these tissues show stress
relaxation and creep. Beyond physiological ranges, soft
tissues usually have a large reserve of strength before
they rupture and fail (43). These features of hysteresis,
relaxation, and creep at lower stress ranges (“physiological”) indicate that biological tissues are inelastic, with
their stress-strain relationship nonlinear. Soft tissues,
however, can be treated as one elastic material in loading,
and another elastic material in unloading (43).
In the physiological state, lung tissues are not unstressed. In fact, the lung does not have a defined stressfree state; unlike most other organs, it is a pressuresupported structure (77). The chest wall and associated
respiratory muscles provide the external distending stress
to maintain the lung state of inflation, whereas the
transpulmonary pressure may vary during breathing but
always remains positive. Thus the mechanical behavior of
the lung depends on the level of the prestress transpulmonary pressure, as well as on the mechanical behavior
of its microstructural elements (138). The parenchymal
microstructure functions as a tension-supported lattice
(78, 91), and the transpulmonary pressure (distending
stress) is transmitted throughout the parenchymal tissues, thus distending all intrapulmonary structures (91).
In the lung, airways and blood vessels are embedded
in and attached to a surrounding tissue that consists of an
interconnected network of thin walls (168). Intraparenchymal vessels and airways exhibit mechanical properties
different from those of the parenchymal tissues in which
they are embedded; therefore, parenchymal distortions
arise during the act of breathing (40, 91). Transpulmonary
pressure acts directly on the elastic surface of the lung,
and this stress is transmitted to internal points of the
organ by the elastic elements. Although the lung is exposed to transpulmonary pressure, its air spaces are distended solely by the force applied on them by surrounding
tissues, as a result of mechanical interdependence. In a
homogeneous lung, all distensible regions are exposed to
transpulmonary pressure, while in nonuniformly expanded
lungs, the effective distending pressure differs from transpulmonary pressure (91, 168) (Fig. 4).
Many efforts have been focused on establishing a
mathematical relation, called the constitutive equation,
which describes the mechanical behavior of the lung, i.e.,
its stress-strain relationship (138, 144). The simplest equation is the linear relationship (Hooke’s law), which contains only two independent coefficients: the bulk modulus, indicating the ability to resist a small uniform expansion, and the shear modulus, indicating the ability to resist
a small isovolume shape distortion (138).
In the continuum elasticity model suggested for lung
parenchyma (168), the shear modulus increases with augmenting distending stress. The effects of a local distur-
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(92), and recruitment-derecruitment of atelectatic alveolar spaces (135). Schurch et al. (126) showed that after
few consecutive cycles, the hysteresis of the surface film
during small-amplitude cycling becomes negligible, suggesting that during tidal breathing the contributions of the
surface film to lung hysteresis are small. In addition,
dynamic properties of parenchymal tissue strips do not
change after loss of cell viability (174). Taken together,
these studies suggest that lung parenchyma mechanics
are most likely dominated by the extracellular matrix
(175). Furthermore, elastance of lung tissue strips is far
less than that of collagen or elastic fibers alone, which
represents a network effect where the total stiffness of a
large network of interconnected springs can be smaller
than the spring constant of individual springs (175). When
matrix strains under an applied load, relative movement
occurs among neighboring fibers, implying that strains at
the microstructural level may not follow strains at the
macroscopic level (96). Yuan et al. (175) showed that
digesting both elastin and collagen resulted in a large
decrease in lung tissue elastance and indicated that the
actual topology of the network must play an important
role in its macroscopic behavior. Tissue mechanics at the
macroscopic level are dominated by the connective fiber
network, whereas interstitial cells play a less significant
role (174). Various network models have been proposed
in the literature, including fiber recruitment type models
(86, 87, 113), the line element model of the alveolar duct
(170), or other geometric models (30).
Suki et al. (142) proposed a mechanistic basis for the
constant-phase-type tissue viscoelastic behavior, i.e., the
so-called “reptation” motion of the collagen-elastin fibers.
The distribution of fiber width and length has been identified as a candidate mechanism at the level of the fiber
network responsible for the macroscopic viscoelasticity
(174). On the basis of the architecture of the microstructure of the lung, slow reptation of fibers could contribute
to the viscoelastic properties of lung tissue (142).
Mijailovich et al. (95) also identified the connective
tissue network as the primary source of lung macroscopic
behavior, whereas a stick-and-slip motion transfers the
load between fibers in close contact. On the other hand,
distinct mechanical states can be observed owing to contractile cells in lung parenchyma (38). Experimental evidence supports that hysteresivity is directly associated
with the cross-bridge cycling rate and the metabolic state
of the cells (39). However, Yuan et al. (174) found nearly
identical mechanical parameters in viable and nonviable
tissue samples, implying that the extracellular matrix may
also play an important role in the mechanical properties
of intact lung tissues. Nevertheless, the authors concluded that this finding does not imply that the cellular
components do not influence parenchymal mechanics,
since tissue stiffness changes in response to different
contractile agents owing to cell contraction (174).
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mechanical behavior of the collagen-elastin-proteoglycan
matrix likely accounts for the main proportion of energy
dissipation during breathing (3, 41, 95). It should be kept
in mind that when fibers are arranged in a network, the
latter can display hysteretic and viscoelastic properties
(21, 22, 123). Furthermore, the elastic properties of collagen and elastic fibers differ to a great extent. Collagen, the
most abundant component, admits only minimal stretching, showing great tensile strength but low compliance.
Conversely, elastic fibers may be stretched by a factor of
2–2.3 in relation to their unloaded lengths, presenting
lower tensile strength than collagen but higher compliance (59, 96, 166).
Different theories try to explain tissue viscoelastic
behavior in terms of the movement of fibers within the
connective matrix. The fiber-fiber interaction theory proposes that energy dissipation occurs not at the molecular
level within collagen and elastin, but, instead, at the level
of fiber-fiber contact and by the shearing of glycosaminoglycans that provide the lubricating film between adjacent
fibers (96). A second theory suggests that the mechanical
properties of the tissue matrix can be understood as a
polymer, whereas viscoelastic behavior occurs because of
conformational changes in the molecules, thus being secondary to the structural disposition of fibers and their
instantaneous configuration during motion (142). This
theory proposes that external stresses cause polymer reptation, a sort of snakelike unfolding of fibers that alters the
configuration of molecules and creates distortions that
dissipate energy (142).
Evidences of distinct tissue mechanical properties
between mouse strains suggest a key role for specific
extracellular fiber composition and the amount of contractile structures in the lung parenchyma. The total
amount of collagen fibers in lung parenchyma strips has
been positively correlated with tissue resistance and elastance, while elastic fiber content has been positively associated with tissue elastance (34). In addition, specific
components of the elastic system may also play a role in
the observed differences in tissue mechanics among species (35, 44, 94). Altogether these evidences suggest that
collagen and elastic fibers directly contribute to lung tissue stiffness and viscosity. It is noteworthy, however, that
not only the absolute amount of fibers constitutes an important factor affecting mechanical behavior, but rather the
organization and/or interaction among these fibers (96, 174).
The better understanding of tissue resistance behavior requires the unfolding of the complexity of interactions between the different structures comprising this
material. The anatomic elements responsible for tissue
hysteresivity, resistance, and elastance are thus far unknown (82). As underlined before, the potential factors
contributing to tissue hysteresis include contractile elements in the lung parenchyma (73, 166), the collagen
elastin matrix (96), the air-liquid interface or surfactant
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chanics (148). Indeed, the rise in ␩ with maturation could
be possibly explained either by the increase in the absolute number of fibers interacting with each other or, alternatively, by changes in the ground substance (148,
149).
E. Mechanical Interactions Between Collagen
and Proteoglycans
Proteoglycans consist of a protein core with large
polysaccharide side chains, the glycosaminoglycans. Glycosaminoglycans interact with collagen, elastin, and cells
probably modulating the formation and/or remodeling of
the connective tissue, but their mechanical roles remain
largely unknown (61). Decorin, a small leucine-rich proteoglycan present in tissues such as the lung with fibrillar
collagen, plays a key role in regulating collagen fibril
formation and the spatial arrangement of collagen fibers
in the matrix (67). It may also take part in the remodeling
associated with respiratory diseases such as pulmonary
fibrosis and asthma, by means of decorin-regulated collagen fibrillogenesis (172). Decorin binds transforming growth
factor-␤, a cytokine implicated in remodeling (158). Additionally, decorin-deficient mice show altered lung tissue
mechanics with increased compliance at higher pressures
and stresses, and smaller airway resistance (45). The
alterations in tissue properties observed in decorindeficient mice are probably secondary to abnormal collagen fibril formation (28, 48).
Proteoglycans can also potentially alter tissue turgor
and viscoelasticity (124). Since it has been proposed that
tissue viscoelasticity reflects the mechanical friction generated as adjacent fibers slide across each another (96),
the nature of this mechanical interaction could be modified by the lubricating film between them. Proteoglycans
coat individual collagen and elastic fibers; hence, alterations in these molecules could possibly affect energy
dissipation at the fiber interface (3). The hydrophilic nature of proteoglycans and glycosaminoglycans attracts
ions and fluid into the matrix (124). Indeed, the swelling
of charged proteoglycans influences the macroscopic mechanical properties of lung tissue strips (3, 25). Although
it seems that the network organization of collagen and
elastic fibers constitutes the dominant factor in the elastic
behavior of lung tissue, interaction of the fibers with
proteoglycans can affect fiber network stability, thus contributing to the tissue mechanical profile (3, 25, 34).
F. Contractile Elements and Tissue Mechanics
During Induced Constriction
Subpleural lung parenchymal strips are commonly
used as a model for the study of mechanical and pharmacological properties of the lung periphery (34, 39, 115, 121,
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How specific remodeling features affect lung tissue
mechanical properties can be partially unshadowed by
lung maturation studies. The maturing lung represents a
naturally occurring model of altered extracellular matrix
that changes rapidly during the postnatal stage. The alveolarization process, characterized by an increase in the
number and size of alveolar walls and a decrease in
alveolar thickness, is followed by a marked increase in
the amount of collagen and elastic fibers during the first
several weeks of life (101). Proteoglycans and glycoproteins also change, including a decrease in hyaluronic acid
and chondroitin sulfate proteoglycan concentrations (148,
149).
Nardell and Brody (101) correlated morphological
changes and extracellular appearance of collagen and
elastin with lung mechanical properties in a rat model of
lung growth. The potential influences of alveolar or airway surface forces and of chest wall were eliminated by
performing saline volume-pressure curves on excised rat
lungs from the perinatal period (day 4) to early adulthood
(day 40). Postnatal lung growth in the rat can be divided
in four stages: lung expansion (between birth and 4 days),
alveolar proliferation (between 4 and 12 days), elastin
accumulation (between 12 and 20 days), and equilibrated
growth (between 20 and 40 days). The authors showed
that changes in lung elastin concentration are associated
with an increase in lung recoil, while lung collagen is
more closely associated with the structural integrity of
the lung as measured by resistance to lung rupture. Furthermore, lung volume tends to follow the course of lung
elastin concentration rather than collagen’s (101).
Another study, examining the viscoelastic behavior
of isolated parenchymal strips from rat lungs at different
ages, showed that tissue resistance and elastance decreases with maturation, while hysteresivity (␩) increases
(149). Since the amount of collagen and elastin rises with
maturation (101), it may be concluded that fiber structure,
orientation, and/or alveolar geometry, rather than the absolute amount of collagen and elastin per se may be
fundamental in determining tissue viscoelastic behavior
(149). Indeed, maturational changes in tissue viscoelastic
behavior in rats are accompanied by changes in the composition and configuration of the alveolar wall, with increasing collagen and elastic fiber contents and diminishing hyaluronic acid and ␣-actin smooth muscle-positive
cells (148). These findings support the concept that the
total amount of extracellular matrix fibers does not respond entirely for the mechanical behavior of the elastic
elements. Indeed, changes in fiber subtype, topology, or
cross-linking with maturation could contribute to it (148).
In addition, proteoglycans and glycosaminoglycans may
add to viscoelastic behavior because they coat the stressbearing fibers and can affect tissue turgor. These molecules may act as “lubricant,” modulating the energy dissipation between fibers and thereby altering tissue me-
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elements can participate: smooth muscle of small airways, smooth muscle in alveolar ducts, and interstitial
contractile cells (59, 73).
It is currently considered that connective matrix is
passively driven by contractile cells along its functional
kernel characteristics to a new operating level without
intrinsic structural changes, thus without significant
changes in the transfer of tissue mechanical properties
(115). On the other hand, contractile cell systems show
prominent hysteretic properties, presenting structural
changes during constriction because of bridge dynamics
(40) and plastic remodeling of the cytoskeleton (49). Authors agree that the connective tissue network dominates
parenchymal mechanics, which can be influenced by the
tone or contraction of interstitial cells (38, 82, 115). Recent findings suggest that mechanical properties of lung
tissue in baseline conditions are actually dominated by
the connective fiber network, whereas interstitial cells
play a less significant role (174). Interestingly, constriction modifies intrinsic mechanical properties of connective matrix by mechanisms diverse from passive stretching (114, 115), suggesting that constriction of some element at the tissue level occurs (98, 99). The mechanical
response to passive length changes obeys the constantphase behavior in the frequency domain (44, 115), while
the Newtonian component of resistance increases only
during constrictor challenge, but not during passive
stretch (115). The mechanical coupling of contractile cells
and fibers depends on the amount of constriction or characteristics of the machinery involved. Contractile cells
modulate the mechanical properties of the connective
matrix (115). Thus energy dissipation at tissue level derives from a complex combination of changes in small
airways, modifications in alveolar ducts, and distortion of
parenchymal tissues secondary to activation of contractile elements (80, 98).
It has also been suggested that tissue response to
bronchoconstrictor agents can be secondary to increased
inhomogeneities in peripheral airway resistance, which
produce an artifactual increase in tissue resistance, suggesting the failure of the model to describe the lungs
under highly heterogeneous constriction (13, 85). Although there is little or no influence of airway inhomogeneities on measurements of lung mechanics in healthy
lungs during a physiological tidal excursion, airway inhomogeneities significantly increase tissue resistance during
agonist-induced constriction (85). Lutchen et al. (85) also
demonstrated that the frequency-dependent behavior of
lung elastance (EL) is markedly influenced by inhomogeneities, rather than a strict consequence of altered tissue
viscoelasticity. Indeed, methacholine challenge increases
lung resistance at all frequencies and also the positive
frequency dependence of EL with minute alterations in its
low-frequency values, thus suggesting little changes in the
true tissue elastance (85). These findings, however, can be
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173), being considered a good proxy of the peripheral
lung tissue (38, 120).
The gas-free isolated parenchymal strip preparation
abolishes the gas-liquid interface, thus eliminating an important stress-bearing system, as well as the effects of
recruitment-derecruitment of atelectatic alveolar spaces.
This preparation brings the experimenter a step closer to
the contractile system and to the extracellular matrix
behavior (38). The attachment-detachment of cross bridges
during volume cycling (41) or the fiber network of the connective tissue (22, 123) could account for the hysteresis
observed in the length-tension curve (41, 96).
The relevance of the parenchymal strip as a proxy for
small airways has been questioned because the strip presents a complex morphology and contains a diversity of
contractile cell types (33, 48). However, it can be considered as a proxy for the integrated contractile response of
the parenchyma itself (38). Indeed, many authors have
used the parenchymal strip as a means of investigating
dynamic mechanical responses to constrictor challenge at
the parenchymal level. Lung periphery constitutes a complex system comprising alveolar walls, bronchioles, and
small vessels. The determination of the precise elements
that respond to contractile stimulus is rather difficult, and
it has been shown that the volume proportions of different anatomic structures, such as amounts of airway, vasculature, and alveolar wall, do not correlate with oscillatory mechanics in subpleural parenchymal lung strips
under baseline conditions (82).
It is also noteworthy that in parenchymal strip preparations lung tissue undergoes uniaxial loading, and
hence, microstructural elements are presumed to deform
only unidimensionally, in contrast to the three-dimensional deformation present in the normally breathing
lung. In the whole lung, macroscale hysteresivity is proportional but smaller than microscale hysteresivity, and
microstructural elements respond both by reorienting and
lengthening. On the other hand, during uniaxial deformation of lung strips, macroscale and microscale hysteresivity are similar, and microstructural components can respond only by lengthening; thus macroscale hysteresitivy
(␩) is a direct reflection of hysteresivity of the microstructural element (38).
The pressure-volume behavior of the lungs can be
changed by several contractile interventions (29, 66, 81).
Many lung responses that have initially been ascribed to
changes in airway caliber have lately been shown to reflect ongoing events at the lung tissue level (79, 83, 117,
159). Lung parenchyma can express diverse mechanical
responses according to the specific agonist present in the
cellular microenvironment, which reveal themselves
mainly in the hysteretic nature of the tissue (38, 84).
Indeed, it has been demonstrated that the hysteretic behavior of pulmonary tissues increases with activation of
the contractile machinery (38). Three types of contractile
LUNG PARENCHYMAL MECHANICS IN HEALTH AND DISEASE
model dependent, since they were observed in a singlecompartment homogeneous model used to characterize
lung constriction.
III. TISSUE MECHANICS IN LUNG DISEASES
A. Lung Parenchyma Remodeling: Micromechanics
of Injured Lungs
Physiol Rev • VOL
tive tissue elements onto the collapsed segment increase
out of proportion in relation to those of more remote
network structures (64).
Analysis by histochemistry demonstrated that lung
collagen content augments in both acute and chronic
interstitial diseases, suggesting that significant remodeling of alveolar tissue occurs even in acute situations
(118). The extracellular matrix remodeling process occurs as a response to lung injury involving all of its
components in a kind of chain reaction. Indeed, the elastic system, a major component of the extracellular matrix,
that plays an important role in maintaining the patency of
the airways and lung elastic recoil is also altered, with
elastic fiber deposition, both in animal models of pulmonary fibrosis (42, 106, 111) and human lung fibrosis (104).
On the other hand, increased elastin destruction occurs in
certain pathological conditions owing to the release of
powerful elastolytic proteases by inflammatory cells
(130). Reactivation of elastin synthesis occurs in response
to increased destruction, but in a disordered manner.
Thus elastosis could also partially respond for the loss
of the normal architecture of the alveolar walls, contributing to the alveolar mechanical dysfunction and remodeling present in acute and chronic interstitial lung diseases (104).
The small leucine-rich proteoglycan decorin regulates collagen fibril formation and spatial arrangement in
the matrix (67). Thus decorin may also play a role in the
remodeling associated with respiratory diseases such as
pulmonary fibrosis and asthma (16). In fact, decorin-deficient mice present decreased airway resistance and increased respiratory compliance in vivo, while in vitro
length-stress curves similarly show increased compliance
of lung strips. The alterations in tissue properties are
likely the result of abnormal collagen fibril formation (45).
Mechanical forces applied to normal lung parenchyma, such as during mechanical ventilation, can also
induce structural and functional changes (19, 165). Lung
cells submitted to different types of force produce proinflammatory mediators (107, 162). In addition, mechanical
forces induce expression of extracellular matrix proteins
by lung tissue (19, 147). Evidences gathered from lung
parenchymal strip oscillation disclosed that tissue elastance and resistance augmented with increasing operating force and decreased with increasing amplitude. Additionally, a rise in force induced early tissue remodeling
(46). In this model, force and amplitude variations simulate in vivo pressure and volume changes, respectively
(65). Moreover, pathophysiological conditions of the lung
may shift the balance of forces so as to chronically alter
the amount of strain imposed on the airways (100, 164).
Tepper et al. (150) demonstrated, in isolated rabbit
intrapulmonary bronchial segments and lung parenchymal tissue slices, that the imposition of physiological
levels of chronic mechanical strain resulted in significant
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During disease states, small-scale heterogeneity in
mechanical properties (such as local shear moduli) increases considerably, which contributes importantly to
local stress distributions (64). The determinants of the
lung parenchymal stress and strain distributions in the
intact thorax depend critically on the lung resistance to a
shape change. Thus the effects of injury on lung mechanical properties become of paramount importance. Several
mechanisms have been suggested to explain the larger
shear modulus of injured lungs, such as interfacial tensions associated with alveolar exudates, increased surface tension, and the consequently increased prestress of
the axial elastin and collagen network, interstitial edema
and matrix remodeling, and scar formation and fibrosis (64).
Damaged lungs present two attributes that account
for their increased risk of deformation injury. First, the
number of airspaces capable of expanding during inspiration diminishes (“baby lung”), increasing the risk of
injury from regional overexpansion, since units that do
not expand during breathing undergo a stronger deforming stress (47, 64). Second, local impedance to lung expansion is heterogeneous because of uneven distribution
of liquid and surface tension in distal airspaces, which
generates shear stress between neighboring, interdependent units that operate at different volumes (64, 91).
Subpleural alveoli of edematous isolated rat lungs present
wavy, flooded walls and contain air pockets of different
sizes and shapes (63). The presence of differently sized air
pockets with diverse radii of curvature implies a nonuniform alveolar gas pressure and/or uneven surface tensions (64). Bachofen and co-workers (8, 9) suggested that
regional differences in the physicochemical properties of
the surfactant could be the source of the nonuniform
surface tension. A maintained nonuniform alveolar gas
pressure may suggest that the air pockets are trapped by
liquid and foam in conducting airways (64).
One should not forget the important phenomenon of
interdependence between elements of the lung parenchyma network, which promotes uniform expansion of
individual units. Stress increases whenever the sum of
forces of the surrounding tissue acts over a smaller surface area. Consequently, when an obstructed unit (e.g., an
alveolus, a lobule, or a lung segment) resists expansion,
the neighboring units exert a large inflationary stress on
it. Moreover, the tension and strain of individual connec-
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DÉBORA S. FAFFE AND WALTER A. ZIN
changes in the passive and active physiological responses
of these tissues. The absence of chronic strain on intraparenchymal airways resulted in smaller, stiffer airways
that generated greater pressures and narrowed to a
greater extent in response to contractile stimulation than
airways that had been subjected to chronic strain. In
addition, the effects of strain were most prominent in the
smaller, more compliant airways (150).
B. Lung Fibrosis
Physiol Rev • VOL
C. Lung Inflammation: Asthma
Various lung diseases are characterized by underlying acute and/or chronic inflammation. Moreover, lung
inflammation has been associated with structural changes
collectively referred to as remodeling. This complex and
variable mechanism occurs in conditions such as acute
lung injury and fibrotic disorders, as described above, as
well as in chronic obstructive pulmonary diseases.
Asthma is characterized by reversible airway obstruction, airway hyperresponsiveness, and airway inflammation. As in many chronic inflammatory disorders,
asthmatic airway inflammation is also believed to cause
tissue injury and subsequent structural changes (58, 133).
These changes have attracted a great deal of interest
because they may account for pathophysiological aspects
in asthma that are poorly addressed with current antiinflammatory strategies (58).
There are evidences that asthmatic inflammation extends to distal airways and lung parenchyma (76, 155, 156,
171). Prolonged inflammation may lead to thickening of
the airway wall, which can be found throughout the bronchial tree including airways ⬍2 mm in diameter (116). In
nonfatal asthma, where airways are only slightly thickened, changes are most pronounced in the small airways
(24, 57). Another characteristic structural change, the
reticular basement membrane thickening with collagen
deposition in the subepithelial space, constitutes an almost pathogenomic feature of asthma, although its clinical significance has not yet been established (133). Moreover, distal airway and lung parenchyma remodeling features have been described in a murine model of chronic
allergic sensitization displaying increased tissue elastance
and resistance (127, 128, 171).
Other elements of the extracellular matrix, such as
proteoglycans and glycosaminoglycans, are altered by remodeling and have been related to changes in tissue
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Pulmonary fibrosis is characterized by abnormal lung
physiology and by the excessive production of extracellular matrix molecules such as collagen, elastin, and proteoglycans (136, 140). Since Rti accounts for a major
proportion of energy dissipation during breathing, defining dynamic tissue behavior in fibrotic diseases represents an important goal (32). Since 1967 it is recognized
that Rti increases in patients with lung fibrosis (7). More
recently, a bleomycin-induced rat model of pulmonary
fibrosis disclosed that Rti rises both in intact animals and
in isolated lung parenchyma strips oscillated in an organ
bath, with similar magnitude changes in vitro and in vivo
(31). Besides the documented increases in collagen and
elastin (136, 140), investigators have focused on changes
in proteoglycans, the macromolecules that comprise the
ground substance of the pulmonary matrix (32). Three
major subclasses of proteoglycans have been described:
hyalectins, which are large molecules such as versican
that form aggregates with hyaluronic acid; basement
membrane proteoglycans such as perlecan; and the small
leucine-rich ones, which include lumican, biglycan, fibromodulin, and decorin (68). The proteoglycans present
many different biological functions: they affect mechanical behavior, influence collagen fiber formation and assembly, modulate cell migration, and interact with various cytokines and growth factors (68). Indeed, a prominent deposition of these molecules is observed in both
granulomatous and nongranulomatous forms of fibrotic
lung disease (16, 17). Evidences suggest that the large
proteoglycan versican (16, 17) or the small fibromodulin
decorin and biglycan are altered in the early stages of
fibrosis (167).
Links between changes in lung function and structure have been described in fibrotic disease. A modest
correlation was observed between the degree of fibrosis
in idiopathic pulmonary fibrosis and the shape of the lung
pressure-volume curve (122). Moreover, positive correlations between volume proportion of collagen and parenchymal strip resistance and elastance were demonstrated
in bleomycin-induced fibrosis in rats, with no correlation
between collagen or elastin and hysteresivity (31). Ebihara et al. (32) described, in bleomycin-instilled rats,
changes in oscillatory and quasi-static mechanics prior to
measurable changes in volume fraction of either collagen
or elastic fibers. Actually, those authors reported important positive associations between changes in structure
and function, namely, biglycan and the three oscillatory
parameters (resistance, elastance, and hysteresivity), suggesting that biglycan acts on lung mechanics by means of
its influence on the matrix assembly (32, 125).
Oscillatory mechanics of lung strips in a murine
model of silicosis showed time-dependent functional
changes, with increased tissue resistance and elastance,
followed by a later rise in hysteresivity. Tissue mechanical behavior was correlated with lung parenchyma inflammation and remodeling, characterized by a process of
fibroelastosis, thus supporting a key role for the elastic
system and its specific components on tissue mechanical
properties (36).
LUNG PARENCHYMAL MECHANICS IN HEALTH AND DISEASE
Physiol Rev • VOL
vative (Hti) parameters determined by forced oscillations
(152). The effects of allergen itself on lung parenchyma
have also been investigated (50). Indeed, the notion that
mechanical abnormalities of the lung parenchyma are
also important in asthma has progressively attracted more
and more attention (127, 128), as suggested by the finding
that parenchymal lung resistance may be significantly
elevated even in patients with spirometric data within
normal limits (71, 72). Lung biopsies also provide evidence that asthmatic inflammatory processes involve the
lung parenchyma (24, 75).
Finally, it is noteworthy that the mechanical stress
developed during asthmatic bronchoconstriction may
also induce remodeling. Epithelial cells and fibroblasts
respond to mechanical stress by increasing collagen synthesis, as well as the ratio between matrix metalloproteinases and tissue inhibitors of metalloproteinases (147).
D. Emphysema
Pulmonary emphysema has been defined by pathological criteria as an irreversible destruction of lung parenchyma distal to the terminal bronchioles with airway
wall destruction and airspace enlargement, not associated
with significant fibrosis (137). The most common cause of
emphysema is cigarette smoking, and the central elements in its definition are the concepts of destruction and
irreversibility of the pathological process (173). Although
environmental toxins affect both proximal airways and
alveolar lung tissue, the two anatomic compartments respond differently: airways present cell proliferation, while
alveolate lung tissue disappears (173). The major mechanisms thought to be responsible for the development and
progression of emphysema include the protease-antiprotease hypothesis, inflammation, oxidative stress, alveolar
cell apoptosis, and matrix remodeling (10, 145, 173). Probably, these are not distinct processes and each can contribute to disease complexity (145).
The most widely accepted hypothesis for tissue destruction in emphysema rests on the imbalance of protease and antiprotease activities, leading to enzymatic
degradation of elastin (10). The concept that tissue destruction results from protease burden, mainly neutrophil
elastase, has relied on the findings in patients deficient in
␣1-antitrypsin, the major inhibitor of neutrophil elastase
(141, 173), in concert with the use of intrapulmonary
instillation of elastolitic enzymes to develop animal models of emphysema (131). However, experimental findings
suggest that neutrophil elastase may not be the principal
protease regulating tissue destruction in emphysema
(145). Macrophage elastase was demonstrated to be sufficient to cause emphysema after chronic inhalation of
cigarette smoke (54), while experimental emphysema can
also be induced by overexpression of collagenase (27) or
impaired synthesis of specific proteoglycans (157).
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mechanics, cellular activity, cytokine function, and fluid
balance. Deposition of the proteoglycans versican, biglycan, and lumican, as well as of the glycosaminoglycan
hyaluronan has been described in asthma (62, 110, 132,
161). The finding of increased amounts of proteoglycans
in the airways of asthmatics and ovalbumin-sensitized/
challenged mice is of particular interest. Proteoglycans
bind with fibrillar collagen and influence the interaction
of collagen fibrils and their assembly (53). They also bind
to other components of the extracellular matrix and
growth factors, affecting cell adhesion and extracellular
matrix deposition (53, 108). The importance of increased
airway extracellular matrix deposition in the pathogenesis of asthma remains uncertain. However, asthma severity and decline in FEV1 have been correlated with subepithelial fibrosis (60). Furthermore, a significant association was observed between enhanced proteoglycan
deposition and increased airway responsiveness (61).
Abnormal elastic fiber network also occurs in the
asthmatic airway, perhaps caused by changes in the elastolytic process (57, 160). Fragmentation of central airway
fibers and marked elastolysis are described in fatal
asthma (57). Furthermore, increased levels of elastase
were found in sputum of asthmatic patients (160). Elastic
fiber fragmentation has also been observed in an animal
model of chronic allergic inflammation (171). Airway geometry, function, and dynamics are subject to these remodeling processes (133).
Data exist suggesting that epithelial damage participates in the proinflammatory process by releasing cytokines, growth factors, and mediators (57, 133). Epithelial
injury can result in a self-sustaining phenotype of wound
repair modulation, by activation/reactivation of the epithelial-mesenchymal trophic unit (18, 70, 151). Collagen,
reticular and elastic fibers, proteoglycans and glycoproteins, all of which contribute to lung remodeling, can be
produced by mesenchymal cells influenced by epithelial
cells. Thus epithelial-mesenchymal interactions play an
important role in extracellular matrix production and
deposition (18, 57, 133). The presence of remodeling features in bronchial biopsy specimens of young children, in
the absence of eosinofilic infiltrates, suggests an early role
for epithelial-mesenchymal trophic interactions, secondary to epithelial injury and stress (37, 105).
Tomioka et al. (152) studied airway and tissue mechanics at baseline and after methacholine challenge in
an allergic murine model that simulates some features of
asthma. They observed that allergic inflammation significantly increased the responsiveness of the lung periphery.
In their model, the rheological properties of lung parenchyma were not altered to any significant extent by inflammation. In contrast, the inflammation caused a sizeable increase in the responsiveness of tissue elastance
and resistance to methacholine measured by the alveolar
capsule, as well as of tissue dissipative (Gti) and conser-
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Physiol Rev • VOL
vage after the induction of acute apoptosis and alveolar
enlargement were able to degrade elastin (5, 173). On the
other hand, oxidative stress decreases the expression of
VEGF coreceptor and an accessory molecule that potentiates VEGF binding (89). In emphysema, free radical
species can be generated by exogenous sources, such as
cigarette smoke, and by endogenous origins, particularly
pulmonary inflammatory cells. In addition, data from
chronic obstructive pulmonary disease (COPD) patients
support the occurrence of an overwhelming oxidative
burden from reactive oxygen species in moderate or severe disease, while healthy smokers and stable patients
show adaptive responses against oxidative stress, probably mediated by glutamate cystenyl ligase, the main regulator of the most important antioxidant glutathione
(173). In fact, the interactions among apoptosis, matrix
proteolysis, and oxidative stress have been proposed as
the final conduit of alveolar destruction in emphysema
(153).
Although most studies suggest that elastin constitutes the major target of destruction in emphysema,
pathophysiological changes can also result from abnormalities in the collagen matrix (69). Indeed, collagen presents higher stiffness and failure threshold than elastin,
protecting the lung from rupture at high volumes. Thus
alveolar wall failure suggests that the collagen network in
the emphysematous lung cannot be normal. Several
MMPs, including MMP-1, -8, and -13, are capable of degrading collagen (145). In addition, cigarette smoke can
undermine the repair function of fibroblasts, epithelial
cells, and mesenchymal cells, yielding persistent abnormalities in tissue structure (109). Elastin and collagen
seem to be the major constituents of the extracellular
matrix, accounting for lung tissue viscoelastic mechanical
properties, and, interestingly, elastic fibers behave more
linearly than collagen fibers (69). In a mouse model of
elastase-induced emphysema, Ito et al. (69) observed increased total collagen content and collagen-related dynamic nonlinearity, while failure stress of isolated parenchymal tissues decreased. These findings suggest that,
despite the increased collagen content, the alveolar walls
and the collagen fibers were likely to be weaker in the
emphysematous lung as a consequence of the process of
degrading and remodeling. In this model, emphysematous
mice also showed increased hysteresivity and lower elastance. Although in normal lung tissue a positive association between hysteresivity and elastin-to-collagen ratio
can be found, emphysematous mice show increased hysteresivity, whereas collagen content also increased. Based on
these results, the authors suggested that remodeling in
emphysema produces weak and viscous alveolar walls
that also fail at lower stress. Thus abnormal collagen
remodeling may play a significant role in lung functional
changes in emphysema (69). Indeed, according to Brewer
et al. (20), normal lungs show a fall in hysteresivity with
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Inflammatory cells, including macrophages, T lymphocytes, B lymphocytes, and neutrophils represent the
best-known source of proteases in the lungs. In addition,
lung tissue destruction can be further enhanced by inflammatory cells recruited by elastin fragments liberated during elastic fibers degradation (131). Cigarette smoke inhalation induces neutrophils, lymphocytes, and macrophages infiltration in the lung, but the specific pathological
role of each inflammatory cell in emphysema remains to be
determined. Lung infiltration of inflammatory cells in emphysema has been attributed to either cigarette smoke/
pollutants or oxidative stress as the result of exposure to
environmental hazards (173). Recent findings suggest,
however, that inflammation could be the result of an
autoimmune attack to lung tissue (2).
Neutrophil elastase and matrix metalloproteinases
(MMPs) are the most studied candidates for protease/
antiprotease imbalance in emphysema. Evidences support a significant role for the macrophage metalloelastase
(MMP-12) and the collagenase MMP-1 in emphysema,
while a role for an imbalance between MMP and tissue
inhibitor of metalloproteinases (TIMP) has also been suggested (173). The targets of proteolitic enzymes and free
radicals liberated by polymorphonuclear cells and monocytes are collagen, elastin, proteoglycans, and ␣1-antitrypsin
(163). In addition to proteases, other factors have been
implicated in tissue destruction leading to emphysema,
such as oxidative stress and apoptosis of lung structural
cells (131). However, one interesting question emerges:
do the inflammatory elements target directly components
of cigarette smoke or is inflammation, rather, a secondary
response to cellular and molecular alterations induced by
cigarette smoke? Each puff of cigarette smoke contains
numerous toxic compounds, free radicals, and potent
oxidants such as hydrogen peroxide, hydroxyl anion, and
organic radicals (154). Tuder et al. (154) underlined the
important similarities between the pathophysiological responses to aging and emphysema owing to chronic cigarette smoking, both presenting oxidative stress and apoptosis as common molecular mechanisms. The authors
suggested that emphysema may recapitulate events underlying accelerated lung aging processes resulting from
failure of lung maintenance and repair (154). In this context, inflammation might represent the response to unrepaired organ injury, rather than the first line of response
to environmental stresses (153, 154).
The finding that decreased vascular endothelial
growth factor (VEGF) or VEGF signaling, an obligatory
lung maintenance factor throughout lung development,
can induce emphysema suggests that alveolar maintenance is required for the structural preservation of the
lung (74, 154, 173). Thus alveolar cell destruction in emphysematous lungs might be caused by apoptosis, possibly unrelated to preceding matrix protease degradation.
Indeed, apoptotic cells retrieved by bronchoalveolar la-
LUNG PARENCHYMAL MECHANICS IN HEALTH AND DISEASE
increasing transpulmonary pressure (PL), while emphysematous rat lungs display constant hysteresivity at all PL
levels. Lung elastance also showed a significantly reduced
dependence on PL in the treated animals. In normal lungs,
the volume-dependent nature of hysteresivity can be attributed to the progressive contribution of collagen at
higher lung volumes (134), since the hysteresivity of collagen is less than that of elastin (95, 175). Thus, taken
together, the results suggest that the PL dependence of
elastance and hysteresivity can signal the early remodeling of elastin and collagen fibers in the alveolar walls during
the development of emphysema (20).
In this review we summarized the basic concepts
involved in energy dissipation during breathing, focusing
on those pertaining to lung tissue behavior. The potential
participating mechanisms, the different models available
for the determination of tissue properties, as well as the
participation of the stress-bearing elements were reviewed. The mechanical properties of lung tissue are
important determinants of lung physiological functions,
being affected in diverse diseases. More recently, models
have tried to deal with dynamic tissue behavior on a
mechanistic basis, and evidences suggest that events at
the microstructural level may not follow those at the
macroscopic level. However, the precise molecular basis
for an integrative biological phenomenon remains unknown.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence:
W. A. Zin, Laboratório de Fisiologia da Respiração, Instituto de
Biofı́sica Carlos Chagas Filho-C.C.S., Universidade Federal do
Rio de Janeiro, Ilha do Fundão, 21941-902 Rio de Janeiro, Brazil
(e-mail: [email protected]).
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