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2015 ; 128
(19
): 2638-45
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Inhibition of Alveolar Macrophage Pyroptosis Reduces Lipopolysaccharide-induced
Acute Lung Injury in Mice
#MMPMID26415803
Wu DD
; Pan PH
; Liu B
; Su XL
; Zhang LM
; Tan HY
; Cao Z
; Zhou ZR
; Li HT
; Li HS
; Huang L
; Li YY
Chin Med J (Engl)
2015[Oct]; 128
(19
): 2638-45
PMID26415803
show ga
BACKGROUND: Pyroptosis is the term for caspase-1-dependent cell death associated
with pro-inflammatory cytokines. The role of alveolar macrophage (AM) pyroptosis
in the pathogenesis of the acute lung injury and acute respiratory distress
syndrome (ALI/ARDS) remains unclear. METHODS: C57BL/6 wild-type mice were
assigned to sham, lipopolysaccharide (LPS) + vehicle, LPS + acetyl-tyrosyl-valyl-
alanyl-aspartyl-chloromethylketone (Ac-YVAD-CMK) and LPS +
Z-Asp-Glu-Val-Asp-fluoromethylketone groups. Mice were given intraperitoneal (IP)
injections of LPS. Drugs were IP injected 1 h before LPS administration. Mice
were sacrificed 16 h after LPS administration, and AMs were isolated. Western
blot analysis for active caspase-1 and cleaved caspase-3, evaluation of lung
injury and a cytokine release analysis were performed. AMs were treated with LPS
and adenosine triphosphate (ATP); caspase-1-dependent cell death was evaluated
using flow cytometry; the apoptosis-associated speck-like protein containing a
caspase recruitment domain (ASC) pyroptosomes were examined by
immunofluorescence. RESULTS: The expression of activated caspase-1 in AMs was
enhanced following LPS challenge compared with the sham group. In the ex vivo
study, the caspase-1/propidium iodide-positive cells, caspase-1 specks and ASC
pyroptosomes were up-regulated in AMs following LPS/ATP stimulation. The specific
caspase-1 inhibitor Ac-YVAD-CMK inhibited the activation of caspase-1 and
pyroptotic cell death. Ac-YVAD-CMK also reduced the lung injury, pulmonary edema
and total protein in bronchoalveolar lavage fluid (BALF). In addition,
Ac-YVAD-CMK significantly inhibited interleukin-?2 (IL-1?2) release both in serum
and BALF and reduced the levels of IL-18, tumor necrosis factor-?± (TNF-?±), High
Mobility Group Box 1 (HMGB1) in BALF during LPS-induced ALI/ARDS. CONCLUSIONS:
This study reported AM pyroptosis during LPS-induced ALI/ARDS in mice and has
demonstrated that Ac-YVAD-CMK can prevent AM-induced pyroptosis and lung injury.
These preliminary findings may form the basis for further studies to evaluate
this pathway as a target for prevention or reduction of ALI/ARDS.
|Acute Lung Injury/*chemically induced/*prevention & control
[MESH]
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