Surfactant Protein D Deficiency Increases Lung Injury
Brooke A. King1and Paul S. Kingma1
1Perinatal Institute, Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
syndrome (ARDS), are major causes of acute respiratory failure with
high rates of morbidity and mortality. Although surfactant protein
clinical studies suggest that this protein may be implicated in the
pathophysiology of ARDS, little is known regarding the function of
intraperitoneal injection of LPS and direct lung injury by intra-
tracheal injection of LPS in wild-type and Sftpd2/2mice to elucidate
the role of SP-D during ALI/ARDS. Results indicate that pulmonary
with wild-type mice. However, the magnitude of this difference was
10-fold greater after indirect lung injury compared with direct lung
injury. After indirect lung injury, there was a 2-fold increase in the
number of pulmonary monocyte/macrophages in the Sftpd2/2mice
when compared with wild-type mice, whereas pulmonary neutro-
phils were not increased. After indirect injury, the concentration of
granulocyte-macrophage colony stimulating factor (GM-CSF) was
contrast, after direct injury, the concentration of GM-CSF was 20-
fold less in Sftpd2/2mice than wild-type mice. Despite increased
mice after indirect lung injury was paradoxically increased. In
conclusion, these results suggest that SP-D inhibits pulmonary
inflammation and migration of peripheral monocyte/macrophages
Keywords: surfactant protein D; acute respiratory distress syndrome;
Acute lung injury (ALI), and its severe form, acute respiratory
distress syndrome (ARDS), are characterized by acute pulmo-
nary inflammation and pulmonary edema. The inflammatory
response in ARDS originates from the loss of vascular endothe-
of protein-rich pulmonary edema, surfactant dysfunction, pul-
monary inflammation, damage to the lung parenchyma and
pulmonary epithelium, and respiratory insufficiency (1). The
outcome of this self-perpetuating process is excessive lung injury
and, in many cases, multiple organ dysfunction syndrome, organ
failure, and death.
ALI/ARDS develops from a variety of clinical disorders that
can be differentiated into those associated with direct lung injury
(e.g., pneumonia, aspiration) and those causing indirect lung
injury (e.g., sepsis, shock). Although the resulting pulmonary
inflammation and damage to the lung parenchyma are similar,
there is a growing body of evidence that suggests that the two
modes of injury have unique underlying pathophysiological
Analysis of bronchoalveolar lavage fluid (BALF) samples
from adult patients with ARDS has demonstrated that, in
addition to inflammation, alterations in lung surfactant function
and composition are present. Whereas pulmonary levels of
surfactant proteins A, B, and C decrease during ARDS, levels
of SP-D increase (3). Moreover, patients with ARDS who have
relatively higher levels of pulmonary SP-D have increased
survival rates, suggesting a vital role for SP-D in ARDS.
SP-D is a member of the collectin family of innate defense
a variety of viral, bacterial, and fungal pathogens (4). SP-D
binding facilitates the uptake and clearance of pathogens from
the lung by alveolar macrophages and neutrophils (5). Although
binding infectious microbes is a critical feature of SP-D function,
animal models of SP-D deficiency indicate that SP-D also
regulates pulmonary immune cells and decreases inflammation
normal surfactant structure and for uptake and recycling of
surfactant by alveolar type II cells (8, 9). Taken collectively, the
changesof SP-D expression during ARDS and the critical role of
SP-D in regulating immune cells and maintaining normal surfac-
tant homeostasis suggest that SP-D plays a critical role in the
body’s response to ARDS.
Therefore, we hypothesize that SP-D attenuates pulmonary
immune cell activation during ALI/ARDS and as a result
reduces pulmonary inflammation and limits lung injury. To
determine if SP-D decreased inflammation during ALI/ARDS,
we induced lung injury in wild-type mice and mice lacking SP-D
(Sftpd2/2) by intraperitoneal or intratracheal injection of LPS.
Whereas SP-D deficiency resulted in increased macrophage
recruitment and a marked increase in pulmonary inflammation
in mice after indirect lung injury, survival was improved in SP-D–
MATERIALS AND METHODS
Studies were performed on 6- to 10-week-old Sftpd2/2and age-
matched Sftpd1/1litter mate wild-type control mice (10). Mice were
During indirect lung injury surfactant protein (SP)-D
inhibits pulmonary inflammation and migration of peripheral
monocyte/macrophages into the lung through granulocyte/
macrophage colony–stimulating factor–dependent path-
ways. However, despite the decreased pulmonary inflam-
mation, SP-D was not associated with decreased mortality
in mice. This study raises the importance of SP-D during
acute lung injury/acute respiratory distress syndrome in-
duced by indirect lung injury and suggests a potential
therapeutic intervention in neonatal and adult patients
with this syndrome.
(Received in original form December 2, 2009 and in final form July 1, 2010)
Supported by National Institutes of Health grant HL089505 (P.S.K.) and Ikaria
Advancing Newborn Medicine Grant for Fellows in Neonatology (B.A.K.).
Correspondence and requests for reprints should be addressed to Paul S. Kingma,
M.D., Ph.D., Section of Neonatology, Perinatal and Pulmonary Biology. Cincin-
nati Children’s Hospital Medical Center, 3333 Burnet Ave. ML7009, Cincinnati,
OH 45229-3039. E-mail: firstname.lastname@example.org
Am J Respir Cell Mol Biol
Originally Published in Press as DOI: 10.1165/rcmb.2009-0436OC on July 16, 2010
Internet address: www.atsjournals.org
Vol 44. pp 709–715, 2011
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