REVIEW
Apoptosis and lung injury
Qing Lu, Elizabeth O. Harrington and Sharon Rounds
Pulmonary Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department ofMedicine Brown Medical School, Providence, RI, USA(Received for publication on August 1, 2005)(Revised for publication on August 20, 2005)(Accepted for publication on September 15, 2005)

Abstract. Apoptosis is important in developmental biology and in remodeling of tissues during repair.
Apoptosis also plays important roles in the progression of many diseases. The cellular and molecularmechanisms of apoptosis, in general, have been extensively demonstrated. However, the causes and theroles of apoptosis of various cell types in the lung are not well understood. We have determined thatadenosine/homocysteine causes lung vascular endothelial cell apoptosis by inhibition of carboxyl
methylation of the small GTPase, Ras, through inhibition of isoprenylcysteine carboxyl methyltransferase (ICMT) activity, leading to inactivation of Ras and the subsequent disruption of focal
adhesion complexes, resulting in cell-extracellular matrix detachment and anoikis. Apoptosis can either
ameliorate or exacerbate lung injury, depending upon the cell type. Although apoptosis of polymorphonuclear leukocytes in the lung prevents inﬂammation and the development of acute respiratory
distress syndrome during acute lung injury, Fas/FasL-mediated alveolar epithelial cell apoptosis promotes acute lung injury and pulmonary ﬁbrosis. Lung epithelial and endothelial cell apoptosis also
contributes to the development of emphysema. This article focuses on elucidating the mechanisms of
adenosine/homocysteine-induced endothelial cell apoptosis. We also review the current understandingof the role of lung cell apoptosis in acute lung injury, pulmonary ﬁbrosis and emphysema. (Keio J Med
54 (4): 184–189, December 2005)
Key words: apoptosis, adenosine/ homocysteine, acute lung injury, pulmonary ﬁbrosis, emphysema

tissues during repair, and in the progression of somediseases.

Overview of Apoptosis
The term apoptosis, originally deﬁned as ‘falling offof leaves from trees’, was ﬁrst used scientiﬁcally to describe energy-dependent cell death by Kerr et al. in
1972.1 Apoptosis or programmed cell death describes a
genetically determined elimination of cells. The process
is initiated by a death signal that tilts the balance between pro- and anti-apoptotic factors. Apoptotic cells
undergo well ordered morphologic and molecularalterations, including cytoskeletal rearrangement,
nuclear membrane collapse, chromatin condensation,
DNA fragmentation, cell shrinkage, plasma membrane
blebbing, and formation of apoptotic bodies.1 In contrast, cells undergoing necrosis swell and lyse, thereby
releasing intracellular contents into the interstitium
leading to an inﬂammatory response.2 Apoptosis isimportant in developmental biology, in remodeling of

Cellular and Molecular Basis of Apoptosis
Various factors, such as Fas ligand (FasL), tumor
necrosis factor-a (TNF-a), metabolite deprivation, DNAdamage, or hypoxia can trigger cell apoptosis. There
are two fundamental signaling pathways, the extrinsic
and intrinsic pathways, by which apoptosis is mediated,as described in Fig. 1. The extrinsic pathway is activatedby external death ligands. The intrinsic pathway istriggered by internal apoptotic signals and involved
in mitochondria. The two pathways merge and sharemechanisms utilizing the aspartate-speciﬁc cysteinyl
protease (caspase) cascades.
The caspase cascade is central to the progression of
apoptosis. To date, 13 mammalian caspases have been

Reprint requests to: Dr. Sharon Rounds, Brown Medical School, Providence VA Medical Center, 830 Chalkstone Avenue, Providence, RI
02908, USA, e-mail: Sharon_Rounds@brown.edu
184

Keio J Med 2005; 54 (4): 184–189

Fig. 1

185

Schematic representation of the cellular and molecular basis of apoptosis.

identiﬁed, which are classiﬁed into initiator caspases
and effector caspases. Initiator caspases, caspase-8, -9,
and -10, are activated by autoproteolysis in response
to death signals and initiate apoptosis.3,4 Effector caspases, caspase-3, -6, and -7, are activated by initiatorcaspases and cleave substrate proteins, culminatingin cell death.4 Over 100 caspase substrates have been
identiﬁed; including inhibitor of caspase-activated
DNase (ICAD), poly ADP-ribose polymerase (PARP),
Bcl-2, lamin, and several cytoskeleton binding proteins.
Cleavage of these proteins causes DNA fragmentation,4 inhibition of DNA synthesis and repair,5 nuclear
membrane disruption and chromatin condensation,6and cytoskeleton collapse.7–11
The extrinsic pathway
Binding of speciﬁc ligand to cell surface or soluble
receptor initiates the extrinsic pathway and apoptosis.
The best characterized ligands and their corresponding
death receptors include FasL/Fas, TNF-a/TNF receptor
1 (TNFR1), AproL/death receptor 3 (DR3) and Apo2L(TRAIL)/death receptor 4 and 5 (DR4, DR5).12,13
Upon ligand binding, adapter proteins are recruited,resulting in association and activation of initiator cas-

pases, which subsequently cleaves and activates effector
caspases or activates Bid-dependent mitochondrial/
intrinsic pathway14,15 and apoptosis ensues.
The intrinsic pathway
Caspase activity is not necessary for apoptosis.16
Mitochondria also play important roles in executing
apoptosis. Exposure to stresses, such as cytotoxic drugs,
oxidants, radiation, and growth factor deprivation,
promotes mitochondrial outer membrane permeabilization (MOMP), resulting in mitochondrial release of
several apoptogenic proteins to the cytosol; including
cytochrome c, Smac, apoptosis-inducing factor (AIF),
endonuclease G, and a serine protease called Omi.17
The released cytochrome c rapidly binds to Apaf-1,
leading to activation of caspase-9, with subsequent
activation of caspase-3, -6, or -7, and culminating in
apoptosis.18,19 Released Smac and Omi activate effector caspases by removal of inhibitor of apoptosis proteins (IAPs).20,21 AIF translocates to the nucleus andinitiates chromatin condensation,22 and endonuclease
G contributes to DNA fragmentation by cleavage ofgenomic DNA.23

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Regulation of apoptosis
Development and tissue homeostasis require a
proper balance between survival and apoptotic signals.
Anti-apoptotic Bcl-2 family members, such as Bcl-2,
Bcl-xL and Mcl-1 heterodimerize nonspeciﬁcally with
pro-apoptotic Bcl-2 family members, such as Bax, Bak,
Bim, and Bid, and sequester them in an inactive state incytoplasm. This sequestration protects against apoptosis by preventing MOMP. Fas-associated death domain(FADD)-like inhibitory proteins (FLIPs) block apoptosis by competing with procaspase-8 for binding withadapter protein FADD.24 In endothelial cells, downregulation of c-FLIP is implicated in extracellular matrix detachment-induced anoikis.25 IAPs prevent apoptosis by binding to effector caspases, rendering them
inactive.26 Death signaling-induced NF-kB activation
promotes expression of various anti-apoptotic proteins,
including Bcl-2, Bcl-xL , FLIPs, IAP-1 and 2, TNFRassociated factor 1 and 2 to protect against apoptosis.27–29
Endothelial Cell Apoptosis
Endothelial cells form a monolayer lining the vasculature. Due to the positioning of the endothelium at
the interface between the blood and surrounding tissue,
the endothelium is exposed to multiple biochemicaland biomechanical stresses, such as lipopolysaccharide(LPS), endotoxin, TNF-a, and oxidative stresses. One
pathological consequence of stresses in the blood vesselis the induction of endothelial cell apoptosis. In this article, we review endothelial cell apoptosis caused byadenosine/homocysteine.
Increased levels of adenosine triphosphate (ATP) or
adenosine may occur in blood vessels upon exocytotic
release of nucleotides from stimulated platelet granules,
during cytolytic release from necrotic cells, or fromendothelial cell membrane transporters.30 We havedemonstrated that elevated levels of ATP or adenosine
promote endothelial cell apoptosis in vitro.31,32
Ectonucleotidase-mediated hydrolysis of ATP and thesubsequent uptake of adenosine were necessary for the
induction of endothelial cell apoptosis.31 We have also
shown that adenosine-induced endothelial cell apoptosis was exacerbated by homocysteine and mimicked byinhibitors of S-adenosyl-L-homocysteine hydrolase.32
In addition, adenosine- and adenosine/homocysteineinduced apoptosis correlated with protein tyrosine
phosphatase-dependent inhibition of p38 mitogenactivated protein kinase (p38 MAPK)33 and degradation of focal adhesion kinase (FAK), paxillin, andp130 CAS proteins, with subsequent disruption of focal
adhesion complexes.8 Importantly, overexpression ofwild type FAK blunted adenosine/homocysteine-

induced endothelial cell apoptosis, while overexpression of mutants of FAK, neither FAT nor FRNK,
which lack the central catalytic domain, didn’t protect
against adenosine- or adenosine/homocysteine-induced
apoptosis.34 Mutation of the autophosphorylation siteof FAK also failed to protect against apoptosis,34
suggesting that kinase activity is required for FAK
protection.
The small GTPases are a superfamily of monomeric
regulatory GTP-binding proteins. The Ras protein was
the ﬁrst characterized and now is known to consist of
5 major classes – Ras, Rho, Rab, Arf, and RAN. Ras
GTPases are molecular switches, in that they are activated when bound to GTP, and inactivated when boundto GDP. This process is regulated by guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and guanine nucleotide dissociation
inhibitors (GDIs). GEFs accelerate the exchange rateof bound GDP for GTP. GAPs enhance hydrolysis ofbound GTP to GDP, whereas GDIs inhibit the exchange of bound GDP for GTP, inhibit GTP hydrolysis,
and prevent membrane association.35 Our studies havedemonstrated that increased adenosine/homocysteine
decreased Ras GTPase activity by inhibiting carboxyl
methylation of this small GTPase through inhibitionof isoprenylcysteine carboxyl methyltransferase(ICMT) activity.36 Transient overexpression of wild
type or dominant active H-Ras blunted adenosine/
homocysteine-induced endothelial cell apoptosis,36
suggesting that Ras GTPase methylation and subsequent activation play an important role in adenosine/
homocysteine-induced endothelial apoptosis.
Thus, it is speculated that increased levels of adenosine and homocysteine promote endothelial cell apoptosis by multiple signaling pathways, resulting in disruption of cell-extracellular matrix interactions andanoikis, as described in Fig. 2.
Apoptosis and Lung Diseases
The lung is a complex organ which includes manydifferent types of cells; including endothelial cells, epithelial cells, ﬁbroblasts, and inﬂammatory cells. Apoptosis can either ameliorate or exacerbate lung injury,
depending upon the cell type. This review article focuses on the effects of apoptosis on acute lung injury,
pulmonary ﬁbrosis, and emphysema.
Apoptosis and acute lung injury
PMN may inﬁltrate lung tissue in acute lung injury
Polymorphonuclear leukocytes (PMN) undergo
apoptosis in vitro. Macrophages phagocytose apoptotic
PMN. It has been suggested that enhanced PMN apop-

Keio J Med 2005; 54 (4): 184–189

Fig. 2

187

Schematic representation of the signal mechanism of adenosine/homocysteine-induced endothelial apoptosis.

tosis may blunt inﬂammation.37 The work of MatuteBello and colleagues has extended this observation toacute lung injury. They found that there are fewer
apoptotic PMN in bronchoalveolar lavage (BAL) of
patients with acute respiratory distress syndrome(ARDS) or at risk of ARDS. Furthermore, BAL from
ARDS patients decreases apoptosis and prolongs
survival in vitro of normal human PMN, due to thepresence of anti-apoptotic factors, such as GM-CSF.38
These observations suggest that lack of PMN apoptosis
may prolong inﬂammatory responses and predispose
the patients to ARDS after acute lung injury.
Fas/FasL-mediated apoptosis causes acute lung injury
The Fas/FasL pathway is an important apoptosissignaling system. Apoptosis mediated by Fas/FasL interaction has been implicated in acute lung injury (ALI)and ARDS. Fas is a 45-kDa type I membrane protein,while FasL is a 37-kDa type II protein. In the lung, Fas
has been found on the surface of alveolar and bronchial
epithelial cells, Clara cells, alveolar macrophages, andmyoﬁbroblasts, while FasL is expressed in neutrophils
and lymphocytes. Alveolar epithelial injury in humans
with ALI or ARDS is associated with local upregulation of the Fas/FasL system and activation of theapoptotic cascade in alveolar epithelial cells.39 Recent

studies show that Fas or FasL deﬁcient mice have lesser
degrees of acute lung injury compared with wild typemice when challenged with intrapulmonary depositionof IgG immune complexes.40 Inhibition of caspase
activity blunts PMN-induced acute lung injury in wild
type mice.40 These results suggest that Fas/FasLinduced apoptosis contributes to acute lung injury.
Fas ligand is cleaved by metalloproteinases to form asoluble form, referred to as sFasL. sFasL accumulates
at sites of tissue inﬂammation and can initiate apoptosisof leukocytes, epithelial cells, and other lung cells.
sFasL is increased in BAL and pulmonary tissue ofpatients with multisystem organ failure (MSOF)39 andin BAL of patients with ARDS.41 Importantly, BAL
from patients with ARDS caused apoptosis of cultured
lung epithelial cells, and this effect was inhibited byblocking the Fas/FasL system,41 suggesting that sFasL
can be released as a biologically active, death-inducing
mediator capable of inducing epithelial apoptosis byinteraction with Fas during acute lung injury. Mechanical ventilation with high tidal volumes of rabbits with
ARDS causes renal and intestinal epithelial cell apoptosis and renal dysfunction, which correlated withincreased plasma sFasL.42 These studies suggest thatsFasL also contributes to failure of other organs in
MSOF.

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Lu Q, et al: Apoptosis and lung injury

Apoptosis and pulmonary ﬁbrosis
Pulmonary ﬁbrosis begins with alveolitis, which progresses to excess collagen deposition and destruction of
normal lung architecture. Epithelial apoptosis and necrosis are increased in lungs of patients with idiopathic
pulmonary ﬁbrosis (IPF).43 Apoptosis has been thought
to be a non-inﬂammatory means of removing injurious
cells thus facilitating lung repair. However, there isincreasing evidence that Fas/FasL-mediated lung epithelial apoptosis induces release of proinﬂammatory
cytokines (such as TNF-a and transforming growth
factor-b1), leading to inﬂammation and progression
from ARDS to ﬁbrosis.44 FasL was upregulated on inﬂammatory cells in BAL from patients with IPF.45 Fas
expression was also increased on alveolar and bronchiolar epithelial cells from patients with IPF.45 sFasL
was signiﬁcantly enhanced in both serum and BAL
from IPF patients.46 Thus, we speculate that Fas/FasLinduced epithelial cell apoptosis may stimulate lungﬁbrosis.
Apoptosis and emphysema
Emphysema is characterized by loss of alveolar capillary septal tissue, resulting in impairment of gas exchange. The imbalance of proteases and anti-proteases
caused by cigarette smoke is important in the pathogenesis of emphysema.47 However, recent work suggests that apoptosis may also be important in thepathogenesis of emphysema. Emphysema lungs displayed apoptosis of both epithelial and endothelial cells
and decreased expression of lung vascular endothelial
growth factor (VEGF) and its receptor 2 (VEGF R2).48
Overexpression of active caspase-3 by intratracheal
instillation causes alveolar epithelial cell apoptosis andemphysema in rats.49 These studies provide direct evidence that epithelial and/or endothelial apoptosis isimportant in the pathogenesis of emphysema. VEGF isabundantly expressed in normal lung and promotes
endothelial cell proliferation. VEGF level is decreasedin emphysema,48 suggesting that lack of VEGF may
result in apoptosis. Indeed, blockade of VEGF receptor
causes apoptosis of alveolar epithelial and endothelial
cells and emphysema in vitro and in vivo.50–52 Thesestudies have expanded the clinical concept of emphysema as a disease of protease-antiprotease imbalance toinclude the idea that programmed cell death could also
be playing a role.
Summary
There are a variety of stimuli that may cause apoptosis via either the extrinsic or intrinsic pathways. Epithelial and/or endothelial apoptosis contributes to acutelung injury, pulmonary ﬁbrosis, and emphysema. How-ever, the mechanisms of endothelial apoptosis in humandisease are not well understood and further study isneeded. Inhibition of apoptosis in a cell-speciﬁc andvascular bed-speciﬁc manner may be potentially therapeutic for some diseases.
Acknowledgements: This work was supported with resources and theuse of facilities at the Providence VA Medical Center and supported
by Rhode Island Foundation Medical Research Grant, American
Lung Association Research Grant RG-1140-N and Parker B. Francis
Fellowship (Q. Lu), HL 64936 and VA Merit Review (S. Rounds),
and HL 67795 and VA Merit Review (E. O. Harrington). Qing Lu is
Parker B. Francis Fellow.

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