Patologia aguda do infarto

1. Acute ischaemic lung injury due to pulmonary vascular
obstruction
Yoshinori Kawabata, Yoshihiko Shimizu, Eishin Hoshi,1
Tomohiko Ikeya,1
Kazuyoshi Kurashima2
& Noboru Takayanagi2
Division of Diagnostic Pathology, Saitama Prefectural Cardiovascular and Respiratory Center, Kumagaya, Saitama,
Japan, 1
Department of Thoracic Surgery, Saitama Prefectural Cardiovascular and Respiratory Center, Kumagaya,
Saitama, Japan, and 2
Department of Respiratory Medicine, Saitama Prefectural Cardiovascular and Respiratory Center,
Kumagaya, Saitama, Japan
Date of submission 24 February 2016
Accepted for publication 2 April 2016
Published online Article Accepted 4 April 2016
Kawabata Y, Shimizu Y, Hoshi E, Ikeya T, Kurashima K & Takayanagi N
(2016) Histopathology 69, 647–654. DOI: 10.1111/his.12979
Acute ischaemic lung injury due to pulmonary vascular obstruction
Aims: We have encountered cases of a distinctive
myxomatous alveolar wall thickening around pul-
monary infarctions, and have termed it ‘acute ischae-
mic lung injury’ (AILI). In this study we determined
if pulmonary infarction is the only cause of AILI and
have elucidated its histological features.
Methods and results: We examined 2941 cases that
underwent lobectomy, surgical lung biopsies for
nodular lesions or autopsies between 1994 and
2014. Cases were divided into pulmonary infarction
and non-infarction groups. The histological features
of AILI sought were lobule-based alveolar wall thick-
ening (myxomatous or fibrous) with epithelial meta-
plasia and negligible inflammation. In order to
characterize AILI further, we performed immunohis-
tochemical staining using several antibodies. Thirty-
four of 69 cases in the infarction group (mean age
57.1 years, 30 males) had AILI, whereas only one
(but with vascular obstruction) of the remaining
2872 in the non-infraction group had AILI. AILI was
located around infarctions. Separation of the epithe-
lial and endothelial basement membranes of the alve-
olar wall was observed in 75% of cases.
Conclusions: AILI is associated almost exclusively
with lung infarction, caused presumably by vascular
obstruction. We consider AILI to represent a distinct
lung lesion other than pulmonary haemorrhage and
infarction.
Keywords: ischaemia, lung cancer, lung infarction, vascular obstruction
Introduction
The main causes of pulmonary infarction have been
identified as pulmonary thromboembolism1–4
and pul-
monary tumours with vascular obstruction.5,6
Vascu-
lar obstruction of the lung classically causes reversible
pulmonary haemorrhage or irreversible pulmonary
infarction.1–4,7
The incidence of pulmonary infarction
was reported recently to be approximately 30% in
cases of acute pulmonary embolism8,9
and 3–10% in
cases of bronchogenic carcinoma.5,6,10
We have encountered previously the presence of dis-
tinctive lobule-sized myxomatous or fibrous alveolar
wall thickening around infarctions,10
including one
case that showed radiologically diffuse pulmonary opac-
ities.11
We speculated that this alveolar wall thickening
may have been due to ischaemia secondary to pul-
monary vascular obstruction (mainly infarction), and
termed this lesion ‘acute ischemic lung injury’ (AILI) to
represent a newly identified lesion. We conducted the
present study in order to test this hypothesis.
Address for correspondence: Y Kawabata, Division of Diagnostic
Pathology, Saitama Prefectural Cardiovascular and Respiratory
Center, 1696, Itai, Kumagaya, Saitama 360-0105, Japan. e-mail:
kawabata.yoshinori@pref.saitama.lg.jp
© 2016 John Wiley & Sons Ltd.
Histopathology 2016, 69, 647–654. DOI: 10.1111/his.12979

2. Materials and methods
S E L E C T I O N O F S T U D Y S U B J E C T S
This study was approved by the Ethical Committee of
the Saitama Prefectural Cardiovascular and Respira-
tory Center (2015013, 5 August 2015).
We examined retrospectively 2142 lobectomy,
bi-lobectomy and pneumonectomy (lobectomy) cases
(males 1503, mean age 66 years), 720 surgical lung
biopsy (SLB) cases (males 432, 63.5) for nodular
lesions and 79 autopsy cases (males 51, 67.5) from
the beginning of 1994 to the end of 2014 for the pres-
ence of pulmonary infarctions (Figure 1A) and AILI
(Table 1). The definition of an AILI unit lesion (AILI
lesion) is focal alveolar wall thickening (myxomatous,
fibrous or a mixture) with epithelial metaplasia and
negligible inflammation, the size of which is up to one
lobule (Figures 1B–D, 2A). AILI lesion is seen often in
proximity to an infarct and the nearby alveoli are
almost normal, as opposed to usual-type acute lung
injury which shows diffuse involvement and luminar
exudation with subsequent organization.12
We divided the above cases into infarction and
non-infarction groups, and examined sex, age and
the presence of AILI lesions in these groups.
E X A M I N A T I O N O F M A C R O S C O P I C F I N D I N G S A N D
T I S S U E S A M P L I N G
Lobectomies
In addition to tumours or other main lesions, the
presence of infarctions (Figure 1A) was investigated.
Several histological specimens were prepared, includ-
ing those directly from and surrounding infarctions.
When no infarction was found, several sections were
prepared routinely from non-tumorous or normal
lung tissue.
Surgical lung biopsy
Several sections were prepared routinely, including
nodules.
Autopsy
The presence of infarctions was determined. More
than 30 histological sections were prepared from both
A B
C D
Figure 1. Infarction and acute ischaemic lung injury (AILI). A 60-year-old male presented with an upper lobe cavitary tumour and periph-
eral ill-defined shadows. A pathological examination showed that adenocarcinoma obstructed the pulmonary artery, resulting in cavity for-
mation, multiple infarctions and AILI. A, Macroscopic features showing haemorrhagic infarction (white arrows), mild centrilobular
emphysema, focal mild consolidation at the pleural side and pleural fibrous thickening (black arrow). Bar = 1 cm. B, Panoramic view show-
ing infarctions (arrows), lobule-based, confluent alveolar wall thickening and centrilobular emphysema. Haematoxylin and eosin staining
(H&E). Bar = 1 cm. C, Diffuse alveolar wall thickening of varying degrees with a preserved lung structure (box, B). Bar = 1 mm. D, Marked
myxomatous swelling of the alveolar wall showing slightly atypical cuboidal metaplasia and spindle cell proliferation (arrow) (box, C).
Bar = 100 lm.
© 2016 John Wiley & Sons Ltd, Histopathology, 69, 647–654.
648 Y Kawabata et al.

3. lungs including abnormal areas and areas with a
normal appearance.
E X A M I N A T I O N O F A I L I
YK searched for AILI lesion and counted the number
of AILI lesions per case using haematoxylin and eosin
staining (H&E). YS examined and confirmed AILI
lesion detected by YK.
Among the AILI cases selected randomly, one or
two representative slides were investigated in more
detail using Elastic van-Gieson staining (EvG) to iden-
tify mural organization13
and by immunohistochemi-
cal staining using mouse anti-human monoclonal
Table 1. Cases reviewed for infarctions and number of cases with infarctions
Methods
Numbers
Male/female
Mean age SD Underlying diseases Number with infarcts and the underlying disease
Lobectomy 2142
1503/639
66.0 10.6
2064: Malignancy (lung cancer, metastasis)
78: Others (41 chronic pulmonary infections,
7 benign tumours, 20 congenital anomalies,
3 postoperative venous obstructions, 7 others)
60
56: Lung malignancy
3: PV injury
1: CPVA with E
SLB nodule 720
432/288
63.5 13.9
309: Malignancy (lung cancer, metastasis)
67: Benign tumours
75: Infectious granulomas
269: Others
7
6: Chronic thromboembolism
1. Sarcoma metastasis
Autopsy 79
51/28
67.5 14.6
16: Pleuro-pulmonary malignancy
30. Non-malignant pulmonary diseases
33. Systemic or other organs
2: Tumour embolism and chronic thromboembolism
Lobectomy: Lobectomy, bi-lobectomy or pneumonectomy, SLB: Surgical lung biopsy; PV injury: Pulmonary venous injury of the other lobe
after lobectomy for malignancy led to re-lobectomy; CPVA with E: Congenital atresia of the basal pulmonary vein with emergency
embolization of the bronchial artery for haemoptysis; SD: Standard deviation.
A B
C D
Figure 2. Histology of infarction and acute ischaemic lung injury (AILI) lesions. A, Diffuse, myxo-fibromatous thickening of the alveolar wall
with cuboidal metaplasia. Haematoxylin and eosin staining (HE). Bar = 200 lm. B, Black elastic tissue and red collagen located in the cen-
tre of the alveolar wall (intra-alveolar wall fibrosis) without mural organization. The same as that shown in 1A. Elastic van-Gieson staining
(EvG). Bar = 200 lm. C, Small numbers of CD3-positive T cells (arrow) were noted in the alveolar wall. Stained with an CD3 antibody.
Bar = 100 lm. D, Small numbers of CD79a-positive B cells and plasma cells (arrow) were noted in the alveolar wall. Stained with an
CD79a antibody. Bar = 100 lm.
© 2016 John Wiley Sons Ltd, Histopathology, 69, 647–654.
AILI due to vascular obstruction 649

4. antibodies for the alveolar epithelium (AE1/AE3),
capillary endothelium (CD34 antibody, NU-4A1), col-
lagen type 4 (PHM-12), vimentin (V9), T cells (CD3
antibody, PS1) and B cells/plasma cells (CD79 anti-
body, JCB117) (each of which was obtained from
Nichirei Biosciences Inc., Tokyo, Japan; concentration
of each antibody is 5–10 lg/ml). Antigens were
retrieved by heat before staining and an automated
immunostainer (Histostainer 36A; Nichirei Bio-
sciences Inc.) was used.
The following semiquantitative estimations were
performed by YK and SY: the thickness of the alveo-
lar wall (the thickest portion, mild: + 40 lm thick,
moderate: ++ 40 lm thick), percentage of the dis-
ruption of epithelial continuity (+ 10%, ++ 10%),
percentage of basement membrane (BM) separation
between the epithelial and endothelial BMs (+ 10%,
++ 10%), percentage of alveolar capillary central-
ization (+ 10%, ++ 10%), vimentin-positive cells
(normal or more than that in normal lungs), and
infiltration of CD3-positive cells or CD79-positive cells
into the alveolar wall ( or + in the three 9200
fields). Differently estimated slides were rechecked,
and a consensus was reached.
S T A T I S T I C A L M E T H O D S
Significant differences between the two groups were
evaluated using the Mann–Whitney U-test (age) and
v2
test (sex and incidence of AILI).
Results
C A U S E S A N D N U M B E R S O F I N F A R C T I O N S
We identified lung infarctions in 69 cases. The causes
of infarctions were primary and metastatic malignan-
cies in 57 cases, tumour embolism in one, chronic
thromboembolism in seven and acute pulmonary
venous injury related to lobectomy and others in four
(Table 1).
C O M P A R I S O N S B E T W E E N I N F A R C T I O N A N D
N O N - I N F A R C T I O N G R O U P S
The infarction group showed male dominance and
a younger age. The incidence of AILI was signifi-
cantly higher in the infarction group [34 (49%)
cases] than in the non-infarction group, which had
one case of nodular sarcoidosis complicated by
thromboembolism and vascular obstruction (0.03%)
(Table 2).
C L I N I C O P A T H O L O G I C A L F E A T U R E S O F A I L I I N 3 4
C A S E S A N D S E M I Q U A N T I T A T I V E E S T I M A T I O N S I N
2 1 C A S E S I N T H E I N F A R C T I O N G R O U P
AILI lesion was identified in 34 cases (30 men, mean
age 57 years) in the infarction group. Twenty-seven
lobectomies were performed and 27 malignancies were
detected. The mean number of AILI lesions was 4.4,
except for two cases in which a large number of conflu-
ent AILI lesions was detected (one tumour embolism
and one congenital anomaly case) (Table 3).
AILI lesions were located around infarctions. In
addition to definition, the lung structure was pre-
served and in 34 cases no mural organization was
observed by EvG (Figure 2B). The degree of alveolar
wall thickness varied (Figures 1D, 2A), with 24% of
cases showing moderate thickness. Diffuse cuboidal
cell metaplasia with occasional atypical regeneration
was observed in all 34 cases.
Immunohistochemical examination was performed
in 21 recent cases. Partial disruption of epithelial
continuity (Figure 3A) was noted in 48% of cases.
The separation of alveolar epithelial and capillary
BMs (Figure 3B) was observed to various degrees
(mild to moderate) in 75% of cases. Centralization of
the capillary (Figure 3C) was also detected to various
degrees (mild to moderate) in 71% of cases. An
increase in the number of vimentin-positive spindle
cells (Figure 3D,E) was noted in myxomatous and
fibrous alveolar walls in all cases. The infiltration of a
small number of CD3- and CD79-positive cells was
found in 38% and 24% of cases, respectively (Fig-
ure 2C,D). The degree of myxomatous and fibrous
swelling correlated generally with the degree of BM
separation and centralization of the capillary. The
degree of myxomatous swelling correlated with that
of percentage of the disruption of epithelial continuity
(data not shown in Table 3).
Table 2. Comparisons between the infarction group and
non-infarction group
Infarction
group
Non-infarction
group Statistics
Numbers 69 2872
Male/female 57/12 1929/943 0.0066 v2
Age (years) 60.2 13.5 65.6 11.6 0.0004 Mann
AILI, n (%) 34 (49.2%) 1 (0.03%) 0.0001 v2
AILI: Acute ischaemic lung injury; Mann: Mann–Whitney.
© 2016 John Wiley Sons Ltd, Histopathology, 69, 647–654.
650 Y Kawabata et al.

5. Discussion
In the present study, we detected AILI in 49% of
cases in the infarction group. In the non-infarction
group, AILI was found in only one case, which was
complicated by pulmonary thromboembolism but no
frank infarction. The histological features of AILI are
characterized by non-inflammatory, myxomatous or
fibrous thickening of the alveolar wall with frequent
BM separation and an increase in the number of
vimentin-positive spindle cells.
The reasons for male dominance and the younger
age in the infarction group currently remain unclear.
AILI was observed almost exclusively in the infarction
group, suggesting that severe local ischaemia due to
vascular obstruction is needed to produce AILI. Early-
stage AILI is characterized by myxomatous swelling,
indicating that fibroblasts in the alveolar wall become
activated, and then synthesize and secrete a precursor
of hyaluronic acid following alveolar wall injury.14
EvG failed to show intraluminar exudation and subse-
quent mural organization, which is observed typically
in non-specific interstitial pneumonia (NSIP),15,16
ALI12
and diffuse alveolar damage (DAD).17
The disruption of epithelial continuity suggests
epithelial erosion, and subsequent atypical epithelial
regeneration is considered. The separation of both
BMs was noted in 83% of cases; however, the under-
lying mechanisms remain unclear. We have reported
previously that pulmonary infarction is followed by
alveolar wall haemorrhage, and showed the diffuse
and complete separation of BMs and centralization of
capillaries in alveolar wall haemorrhage and pul-
monary infarction.10
The separation of BMs may be
explained partly by the mechanical pressure of blood
in the alveolar wall. The separation of BM and cen-
tralization of capillaries were not observed with DAD
or acute lung injury (our unpublished data). The par-
tial disruption of the epithelium and endothelium by
dropping has been reported in alveolar wall haemor-
rhage.10
In AILI, the endothelium was clearly
stained.
Because various mesenchymal cells and lympho-
cytes became positive for vimentin, we examined
Table 3. Clinicopathological features of AILI in 34 cases and a semiquantitative estimation in 21 cases in the infarction
group
Sex Male 30, female 4
Age 29–85, mean 57.1
Methods 27 Lobectomy, 5 SLB, 2 autopsy
Underlying disease 27 Lung malignancy (14 Sq, 9 Ad, 4 others), 5 TE, 1 tumour embolism, 1 congenital anomaly
Number of AILI lesions 1–10, mean 4.4, excluding the 2 cases below
One autopsy case of tumour embolism and 1 lobectomy case of congenital atresia of the basal pulmonary
vein following bronchial arterial embolization showed a large number of confluent AILI lesions and
multiple infarctions
Characteristics of AILI
Examined
numbers
Negative/positive
and degree
Results
(positive %)
Mural organization 34 /+ 34/0 (0)
Thickness of the AW 21 /+/++ 0/16/5 (100)
Epithelial disruption 21 /+/++ 11/9/1 (48)
Separation of the BM 20 /+/++ 5/11/4 (75)
Centralization of the CAW 21 /+/++ 6/11/4 (71)
Vimentin 21 Normal/increase 0/21 (100)
CD 3-positive cells 21 /+ 13/8 (38)
CD79-positive cells 21 /+ 16/5 (24)
AILI: Acute ischaemic lung injury; SLB: Surgical lung biopsy; Sq: Squamous cell carcinoma; Ad: Adenocarcinoma; TE: Thromboembolism;
AW: Alveolar wall; BM: Basement membrane; CAW: Capillary of the alveolar wall; OO: Obstructive organization.
© 2016 John Wiley Sons Ltd, Histopathology, 69, 647–654.
AILI due to vascular obstruction 651

6. A B
C E
D
Figure 3. Immunohistochemical features of infarction and acute ischaemic lung injury (AILI) lesions. A, A markedly thick alveolar wall
lined by atypical cuboidal cells with occasional epithelial disruption (arrow). Stained with AE1/AE3. Bar = 100 lm. B, Clear separation of
the epithelial basement membrane (arrow) and endothelial basement membrane (dotted arrow). Stained with an anti-type IV collagen anti-
body. Bar = 100 lm. C, Capillaries were located in the centre of the alveolar wall. Stained with an CD34 antibody. Bar = 100 lm. D,
Increase in the number of vimentin-positive cells including spindle cells (arrow) in the myxomatous alveolar wall. Stained with an anti-
vimentin antibody. Bar = 100 lm. E, Increase in the number of vimentin-positive cells including spindle cells (arrow) in the fibrous alveolar
wall. Stained with an anti-vimentin antibody. Bar = 100 lm.
Suspected sequences of acute ischemic lung damages
1. Alveolar hemorrhage
2. AILI
3. Pulmonary infarction
of the alveolar wall
Begins with myxomatous swelling
Begins with alveolar wall hemorrhage
following alveolar haemorrhage and death
No death of epithelium
No residual lesion,
but hemosiderosis
Interstitial fibrosis
Organization with scar
or endothelium
Figure 4. Proposed sequences of acute ischaemic lung damage (AILI). (1) Alveolar haemorrhage. When damage to the capillary endothelium
is mild and there is no cell death in the capillary endothelium or alveolar epithelium, only alveolar haemorrhage occurs. There is only resid-
ual haemosiderosis. (2) AILI. Moderate injuries in the capillary endothelium may cause exudation into the alveolar walls and activate fibrob-
last, followed by myxomatous swelling and subsequent fibrogenesis in the alveolar walls. (3) Pulmonary infarction. When damage to the
capillary endothelium is severe, alveolar wall haemorrhage occurs and is followed by tissue necrosis/infarction.
© 2016 John Wiley Sons Ltd, Histopathology, 69, 647–654.
652 Y Kawabata et al.

7. spindle cells. An increase in the number of vimentin-
positive spindle cells was reported previously in myx-
omatous and even fibrous alveolar walls, and sug-
gests an increase in the number or activation of
fibroblasts.14
Inflammatory cell infiltration, particu-
larly that by B cells/plasma cells, was not observed or
was negligible, in contrast to NSIP.15,16
Vascular obstruction due to lung tumours and
tumour embolism is a subacute or chronic process,
and is suspected when vascular stenosis has exceeded
some critical point and acute infarction or AILI
occurs. Therefore, we termed this phenomenon AILI.
Incomplete or partial infarctions have already been
described.1,18
Hampton et al. proposed the concept of
‘incomplete infarction with subsequent resolution’;
however, pathological findings were not shown.1
Cor-
rin and Nicholson used the term ‘partial infarction’,
which was characterized by capillary destruction, pul-
monary haemorrhage, acute inflammation and a pre-
served basic architecture. Furthermore, apparent
complete resolution was confirmed by a radiological
examination.18
We consider AILI to differ from partial
infarction and suspected alveolar wall fibrosis to per-
sist because of the presence of a fibrously thick wall.
Reversible pulmonary haemorrhage and irreversible
pulmonary infarction are known to follow pulmonary
thromboembolism. Herein we present AILI as an
intermediate lesion between haemorrhage and infarc-
tion (Figure 4).
AILI in pulmonary malignancies is not clinically
significant because it is merely a shadow around pul-
monary infarctions. However, when a large number
of AILI lesions are noted in cases of tumour embolism
and thromboembolism, bilateral diffuse ground-glass
opacities and small nodules may be seen, as we have
reported previously;11
in such cases the clinical differ-
ential diagnosis is diffuse interstitial lung disease. It is
important to differentiate AILI from DAD;17
the latter
may show alveolar wall oedema and widening with
overlying epithelial metaplasia but other features,
notably hyaline membrane formation and exudate/or-
ganization, are typically present. Tumour embolism
and thromboembolism may complicate DAD.19,20
As we have encountered only a limited number of
autopsy cases of pulmonary tumour embolism and
thromboembolism, we were unable to estimate the
incidence of infarctions, AILI and haemorrhage or
determine their radiological features in the present
study. Furthermore, clinical significance was not esti-
mated, except for one case report.11
The mechanisms
underlying BM separation and the activation of
fibroblasts were not elucidated and, thus, necessitate
further investigation.
In summary, AILI is a distinct lesion related to vas-
cular obstruction. Its main histological features are
myxomatous or fibrous thickening of the alveolar
wall, the frequent separation of BMs and activated
fibroblasts. We propose that AILI represents a form of
vascular ischaemic injury in the lung that is interme-
diate between alveolar haemorrhage and pulmonary
infarction.
Acknowledgements
We are very grateful to Dr Thomas V. Colby (Depart-
ment of Laboratory Medicine and Pathology, Mayo
Clinic, Scottsdale, AZ, USA) for his helpful comments
and suggestions.
Conflicts of interest
The authors declare no conflicts of interest and no
funding disclosures.
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