Am J Physiol Lung Cell Mol Physiol 291: L297–L300, 2006.
First published April 28, 2006; doi:10.1152/ajplung.00138.2006.
EB2006 SYMPOSIUM REPORT
Cell signaling underlying the pathophysiology of pneumonia
Alice S. Prince,1 Joseph P. Mizgerd,2 Jeanine Wiener-Kronish,3 and Jahar Bhattacharya4
1
Department of Pediatrics and Pharmacology, Columbia University, New York, New York;
2
Harvard School of Public Health, Boston, Massachusetts; 3Department of Anesthesia and
Perioperative Care, University of California San Francisco, San Francisco, California; and 4Lung
Biology Laboratory, Columbia University & St. Luke’s-Roosevelt Hospital Center, New York, New York
Prince, Alice S., Joseph P. Mizgerd, Jeanine Wiener-Kronish,
and Jahar Bhattacharya. Cell signaling underlying the pathophysiology
of pneumonia. Am J Physiol Lung Cell Mol Physiol 291: L297–L300,
2006. First published April 28, 2006; doi:10.1152/ajplung.00138.2006.—
The symposium addressed the burgeoning interest in fundamental mech-
anisms underlying the onset of pneumonia. Bacteria exploit the lung’s
innate immune mechanism, resulting in pathophysiological cell signaling.
As a consequence inflammation develops, leading to pneumonia. New
mechanisms have been identified by which bacteria or bacterial products
in the airway induce cross-compartmental signaling that leads to inflam-
matory consequences. The speakers addressed activation of the transcrip-
tion factor, NF-␬B occurring as a consequence of bacterial interactions
with specific receptors, such as the Toll-like receptors and the TNF
receptor 1 (Prince), or as a consequence of cytokine induction (Mizgerd).
Also considered were mechanisms of bacterial virulence in the clinical
setting (Wiener-Kronish) and the role of alveolar-capillary signaling
mechanisms in the initiation of lung inflammation.
PATHOGEN-HOST INTERACTIONS AT THE AIRWAY
EPITHELIAL SURFACE1
Complex signaling circuits are activated by bacterial contact
with airway epithelial cells that initiate chemokine expression
to recruit phagocytes to the region of infection. Bacterial
ligands also activate anti-inflammatory signals, resulting in
receptor shedding, cytokine neutralization, and macrophage
recruitment. Toll-like receptors (TLR) are critical in signaling
bacterial infection. The Prince group has addressed the role of
TLR2, which is apically displayed on airway cells and is of
particular interest since it can respond to diverse types of
bacteria. The TLR2 repertoire is further broadened through
association with asialoGM1, which provides the GalNAcGal
receptor for Pseudomonas aeruginosa pili and flagella, as well
as for many other pulmonary pathogens (27). AsialoGM1 and
TLR2 are colocalized within lipid rafts and are actively mobi-
lized to the apical surface of infected airway cells where they
initiate activation of NF-␬B, as well as activator protein-1,
cAMP response element binding protein, and CCAAT en-
hancer-binding protein, and release of IL-8, granulocyte-
macrophage colony-stimulating factor, IL-6, and MUC-2.
The TNF-␣/TNF receptor 1 (R1) cascade (Fig. 1) is also
activated in airway epithelial cells by bacteria, specifically by
Staphylococcus aureus protein A, which is especially abundant
on bacteria isolated from patients with pneumonia. Bacteria
induce the mobilization of TNFR1 to the surface of the respi-
1
Presented by Alice Prince.
Address for reprint requests and other correspondence: J. Bhattacharya, 432
W. 58th St., Rm. 509, New York, NY 10019 (e-mail: jb39@columbia.edu).
http://www.ajplung.org 1040-0605/06 $8.00 Copyright © 2006 the American Physiological Society
ratory epithelial cell. The protein A-TNFR1 interaction is
essential for the pathogenesis of staphylococcal pneumonia (5).
Downloaded from http://ajplung.physiology.org/ by 10.220.33.2 on October 31, 2017
Stimulation of TNFR1 induces chemokine (IL-8) and cytokine
(IL-6) production by airway cells but also activates TNF-␣-
converting enzyme (TACE) or ADAM-17, a protease that
targets the ectodomains of many substrates including TNF-␣,
TNFR1, and IL6R␣. TACE-mediated shedding of IL-6R␣ and
its association with free IL-6 and cell surface-associated gp130
initiates “transsignaling,” a mechanism that stops polymorpho-
nuclear leukocyte (PMN) chemokine expression and induces
macrophage chemokine, CCL2, production (6). These events
trigger the resolution phase of an acute inflammatory response.
TACE-associated release of TNFR1 also neutralizes free
TNF-␣ and limits the potential for ongoing TNF signaling.
Bacterial induction of the TNF cascade has important anti-
inflammatory effects that serve to limit the extent of PMN
recruitment. Thus the airway epithelium, even in the absence of
signals from professional immune cells, actively participates in
both the recruitment and regulation of PMN mobilization to
areas of bacterial contamination.
BACTERIA-INDUCED CYTOKINE SIGNALING2
Neutrophil recruitment and plasma extravasation contribute
to both bacterial clearance and inflammatory injury (Fig. 2).
These innate immune functions require the expression of ad-
hesion molecules, chemokines, and other mediators, induced
by receptors for microbial products and host factors such as
cytokines. Bacteria-induced cytokine signaling determines the
pathophysiological outcome of pneumonia.
Cytokines regulate expression of many relevant genes by
activating transcription factors such as NF-␬B. The Mizgerd
group has shown that in response to bacterial stimuli in the
lungs, two NF-␬B proteins translocate to nuclei, RelA and p50
(10, 19). RelA is essential for the transcription of chemokines
and adhesion molecules that mediate neutrophil recruitment,
and interrupting RelA compromises the clearance of bacteria
from mouse lungs (1). In contrast, p50 limits expression of
these and other proinflammatory genes (16, 17). Interrupting p50
increases mortality by exacerbating acute lung injury despite
effective bacterial clearance (16). Thus a healthy outcome from
lung infection requires the balance of two NF-␬B proteins, RelA
and p50, with opposing actions on gene expression.
2
Presented by Joseph Mizgerd.
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
L297
L298 EB2006 SYMPOSIUM REPORT

Fig. 1. Staphylococcus aureus protein A activates

the classical TNF-␣ signaling cascade by interacting
with TNF receptor 1 (R1) displayed on the surface
of airway cells resulting in chemokine, cytokine, and
mucin expression. In addition, protein A stimulates
the protease activity of TACE (tumor necrosis fac-
tor-converting enzyme or ADAM-17), which
cleaves and releases soluble (s) TNFR1 from the
airway surface. sTNFR1 is then available to neutral-

Downloaded from http://ajplung.physiology.org/ by 10.220.33.2 on October 31, 2017

ize free protein A and TNF-␣ ligands. TRADD,
TNFR-associated death domain protein; TRAF,
TNF receptor-associated factor; RIP, receptor-inter-
acting protein; ATF, activating transcription factor.

The early response cytokines TNF-␣ and IL-1 (␣ and ␤)
activate NF-␬B. A lack of signaling either from TNF-␣ or from
both IL-1␣ and IL-1␤ is of little consequence during Esche-
richia coli or Streptococcus pneumoniae pneumonias (10, 18,
20). Unlike mice deficient in one or the other pathway, mice
without signaling receptors for all three early response cyto-
kines have pronounced changes during pneumonia, and their
phenotypes differ depending on the infecting organism. In
response to E. coli, there are modest defects in NF-␬B activa-
tion or bacterial clearance, but mice are significantly protected
from inflammatory injury (15). In contrast, during S. pneu-
moniae pneumonia, interrupting these signaling pathways sub-
stantially decreases NF-␬B activation, innate immunity gene
expression, and bacterial clearance (10). Thus, for both bacte-
ria examined, TNF-␣ and IL-1 have essential but overlapping
roles. However, the signaling pathways dependent upon them
and their functional significance are microbe specific.
Other cytokines and transcription factors are also important
during pneumonia. For example, IL-6 is essential to neutrophil
recruitment and bacterial clearance (9). Activation of STAT3
depends in part on IL-6 during E. coli pneumonia (9), and
STAT3 protects lungs from injury (8). Although IL-6 and
STAT3 are functionally significant, their regulation and mech-
anisms of action during pneumonia remain to be determined.
Finally, cytokines are influential beyond transcription, and
posttranscriptional regulation of innate immunity genes will
likely emerge as critical to the pathophysiology of pneumonia.
P. AERUGINOSA INFECTION: CLINICAL CONSIDERATIONS3
The use of clinically isolated P. aeruginosa in experiments
is prudent because strains isolated from patients have more
genetic diversity than strains utilized in the laboratory. P.
aeruginosa is a useful bacteria to use in experiments of acute
lung injury because it is commonly found in patients who are
ventilated and who have acute lung injury (3), and it is
3
Presented by Jeanine Wiener-Kronish.

Fig. 2. Neutrophil recruitment and plasma ex-

travasation, as observed above 24 h after infec-
tion of mouse lungs, contribute to bacterial
clearance and inflammatory injury and require
the expression of adhesion molecules, chemo-
kines, and other mediators regulated by bacteria-
induced cytokine signaling.

AJP-Lung Cell Mol Physiol • VOL 291 • SEPTEMBER 2006 • www.ajplung.org

 EB2006 SYMPOSIUM REPORT
associated with a higher mortality in patients with nosocomial
pneumonia than other bacteria (2).
P. aeruginosa has extensive genetic variability, allowing it
to thrive in a wide variety of environments. The available
genome sequence information on P. aeruginosa provides in-
formation on one P. aeruginosa strain, PAO1, a laboratory
strain. Comparisons of strains to PAO1 have shown that a more
virulent strain, PA14, has two pathogenicity islands, PAPI-1
and PAPI-2 (7). Notably, the large PAPI-1 island is absent
from PAO1, and only part of PAPI-2 is in PAO1 (30). Four
genomic islands have been identified in P. aeruginosa:
PAGI-1, PAGI-2, PAGI-3, and the flagellum island (4). These
islands can confer virulence characteristics, and they appear to
be only in certain strains of P. aeruginosa (4).
ExoU appears to be on an 80-kb island (29), and although it
appears that the genomic content of different isolates of P.
aeruginosa genes that encode virulence determinants are
highly conserved, strains appear to contain either exoS or exoU
but not both genes. Strains that contain exoU are associated
with a poor clinical outcome and increased rates of mortality
(22), hence the rationale for evaluating specific strains associ-
ated with lung injury in patients and comparing them to strains
from patients without lung problems.
Bacteriophages can also bring genetic information to various
bacterial strains. Two prophages, Bacto1 and Pf1, were found
in the PAO1 genome (28).
Besides the pathogenicity islands or genomic islands, P.
aeruginosa has multiple other mechanisms for virulence. Cell-
associated virulence factors include pili, flagella, lipopolysaccha-
ride, and a variety of fimbrial-related molecules (23). P. aerugi-
nosa also produces products via the type I and type II secretory
systems. These include hydrogen cyanide, proteases, neuramini-
dase, and elastase. These products are produced by the bacteria
and released into the environment. P. aeruginosa also intoxicates
eukaryotic cells by directly injecting toxins into the cytosol via the
type III secretion system. The four toxins injected include ExoS,
ExoT, ExoY, and ExoU. In vivo ExoU toxicity can be suppressed
with phospholipase A2 (PLA2) inhibitors, suggested that ExoU
has phospholipase A activity (23). ExoU possesses a conserved
domain homologous to patatin, a soluble storage protein of potato
tubers. Interestingly, patatin is mainly stored in plant vacuoles as
an inactive enzyme and is activated upon environmental stress or
pathogenic infection. ExoU also has residues that align with
human cytosolic phospholipase A2 (cPLA2) and calcium-indepen-
dent PLA2 (24). On the basis of site-specific mutagenesis of S142
or D344 to alanine, the prediction is that ExoU belongs to a family
of enzymes that utilize a catalytic dyad (24). The substrates for
ExoU appear to be phospholipids and neutral lipids (24). It is
believed that the amino-terminal half of ExoU contains the cata-
lytic domain. Notably, ExoU requires a host cell factor, which so
far has not been identified (24).
Nearly 2,000 strains of P. aeruginosa from ⬃200 neonates,
pediatric, and adult intubated, ventilated patients have been
collected. Strains and the communities of bacteria in the
endotracheal aspirates of these patients are being characterized.
Strains of P. aeruginosa that are newly acquired in the hospital
differ from those that patients have chronically. Virulence of
the strains from patients with and without lung injury is being
evaluated.
AJP-Lung Cell Mol Physiol • VOL
L299
ALVEOLAR-CAPILLARY SIGNALING IN THE INITIATION OF
LUNG INFLAMMATION4
The initiation of pneumonia induced by inhaled bacteria is
attributable to the transmission of an inflammatory signal from
the distal airway to the vascular compartments. Thus introduc-
tion of bacteria such as P. aeruginosa, or of bacterial products
in the airway, induces leukocyte migration into the alveolus
within 3– 4 h (26). This time course matches the time course in
which chemokines such as TNF-␣ are secreted from alveolar
macrophages, thereby providing the chemotactic signal for
leukocyte recruitment (11, 13, 26). Because the airway and
vascular compartments are separated by epithelial and endo-
thelial barriers that restrict and, possibly, inhibit direct diffu-
sion of chemokines between the compartments, it follows that
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the chemotactic signal has to be vectorially transmitted by
cross-compartmental signaling.
The Bhattacharya group considered the role of the cytosolic
Ca2⫹ as the conveyor of the inflammatory signal from the
alveolus to the adjoining capillary (12). The group established
the isolated, blood-perfused rat lung for real-time, optical
imaging of the alveolocapillary region (Fig. 3). By means of
catheter and micropuncture techniques, respectively, these au-
thors separately loaded alveolar epithelial and capillary endo-
thelial cells with the Ca2⫹ fluorophore, fura 2. Ratiometric
imaging provided quantifications of the cytosolic epithelial and
endothelial Ca2⫹ concentrations.
Microinjection of a TNF-␣ bolus in the alveolus generated
rapid Ca2⫹ increases not only in the alveolar epithelium but
also in the capillary endothelium, revealing alveolar-capillary
signal transmission (12). A potential artifact of the micropunc-
ture technique, namely alveolar leakage, was ruled out by a set of
studies that included the demonstration that the TNF-␣ effect
could be blocked by pretreating the alveolus with an antibody that
4
Presented by Jahar Bhattacharya.
Fig. 3. Alveolar-capillary region of a rat lung viewed by 2-photon microscopy.
A, alveolus; V, venular capillary. Endothelial cells (arrow) lining a venular
capillary and epithelial cells (double arrows) lining the alveolar wall are clearly
evident (courtesy Jens Lindert).
291 • SEPTEMBER 2006 • www.ajplung.org
L300 EB2006 SYMPOSIUM REPORT
blocks ligation of TNF-␣ receptor, TNFR1. Pretreating the cap-
illary with the antibody failed to block the signaling effect induced
by alveolar TNF-␣. Furthermore, TNF-␣ injected in the capillary
failed to induce epithelial Ca2⫹ increases in the alveolus. These
findings point to the vectorial specificity of the TNF-␣-induced
alveolar-capillary signal transmission.
A consequence of the alveolar-capillary signaling was the
surface expression of the leukocyte adhesion receptor, P-
selectin, in capillary endothelium. Endothelial P-selectin is
normally held in intracellular vesicles. Increase of Ca2⫹ or
H2O2 causes P-selectin expression (21), which marks proin-
flammatory endothelial activation. Alveolar TNF-␣ increased
capillary P-selectin expression in adjoining capillaries within 5
min (12), indicating that the cross-compartmental inflamma-
tory signaling is rapid.
Characteristically, the alveolar epithelial Ca2⫹ response con-
sisted of high-amplitude Ca2⫹ oscillations that were absent in
the capillary endothelial response. This difference reflected
different patterns of Ca2⫹ mobilization in the two cell types.
Thus, while the epithelial response was consistent with Ca2⫹
release from endoplasmic reticular stores, the damped endo-
thelial response pointed to direct Ca2⫹ entry. Externally ap-
plied arachidonate causes direct Ca2⫹ entry (14). Consistent
with this possibility, pretreating the alveolus with inhibitors of
the arachidonate precursor cPLA2 blocked the TNF-␣-induced
alveolar-capillary Ca2⫹ transmission (12). Details of signaling
intermediates downstream of cPLA2, in particular the role of
oxidants (25), are under evaluation.
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