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Kovacs et al. Vessel Plus 2018;2:15 I http://dx.doi.org/10.20517/2574-1209.2018.06 Page 5 of 9
[20]
A, or combined inhibition of HDAC3 and -6 prevents the LPS-mediated endothelial barrier dysfunction .
More importantly, combined pharmacological inhibition of HDAC3 and -6 protected against LPS-stimulated
[20]
inflammation, capillary permeability, and structural abnormalities in murine model of ALI .
[63]
HDAC inhibition has been shown to ameliorate the inflammatory responses associated with ALI. Ni et al.
reported that broad HDAC inhibitor, butyrate markedly diminishes the pulmonary inflammation in LPS-
induced ALI in mice. LPS administration induces histopathological changes in murine lungs, increases
the production of TNF-α, IL-1β and NO, as well as increases MPO activity and NF-κB p65 expression that
[63]
are significantly attenuated by butyrate pretreatment . The lung edema is markedly reduced by butyrate,
[64]
[63]
indicating its protective effect on the LPS-induced ALI . Zhang et al. further confirmed the beneficial
effect of butyrate on lung injury. They found that two structurally unrelated HDAC inhibitors, sodium
[64]
butyrate (SB) and TSA diminished the sepsis-induced lung edema and leukocyte infiltration in lung tissue .
In addition, SB and TSA decrease the expression of ICAM-1 and E-selectin in lung tissue and reduces plasma
[64]
levels of IL-6, indicating that these HDAC inhibitors attenuate sepsis-induced inflammatory lung injury .
Other group has also demonstrated that early administration of broad-spectrum HDAC inhibitor valproic
acid (VPA) significantly reduces the levels of IL-6 and tumor necrosis factor in bronchoalveolar lavage (BAL)
[65]
fluid and in plasma as well as improves survival in murine ALI model in gram-negative pneumonia . They
also showed that VPA reduces the production of proinflammatory cytokines and the neutrophil influx into
[66]
the pulmonary parenchyma and alleviates the host systemic and pulmonary inflammatory responses .
In addition, the HDAC inhibitor VPA decreases the MPO activity reducing the lung injury induced by the
[66]
bacterial infection and improves the histopathologic changes related to ALI . VPA has also been reported
to prevent ALI induced by ischemia-reperfusion (I/R) in rat lungs. I/R significantly increases the lung edema,
pulmonary arterial pressure, lung inflammation and the concentrations of the inflammatory mediators
[TNF-α, cytokine-induced neutrophil chemoattractant-1 (CINC-1)] in bronchoalveolar lavage fluid (BALF).
Pretreatment with VPA diminishes the I/R-caused alterations via increased heme oxygenase-1 (HO-1)
[67]
[68]
activity that is an essential protective regulator in lung injury . Lu et al. demonstrated that HDAC
inhibitors, suberanilohydroxamic acid (SAHA) and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-
oxoheptyl] benzamide significantly decreases early neutrophilic inflammation in murine model of ALI. They
showed that these inhibitors are able to block the leukotriene A4 hydrolase (LTA4H) activity and to prevent
the leukotriene B4 (LTB4) biosynthesis suppressing the LPS-induced neutrophils migration and infiltration
into the murine lungs as well as reduces the production of inflammatory mediator (e.g., TNF-α, IL-1β, and
[68]
IL-6) induced by LPS .
HDAC6 plays an important role in the cigarette smoke extract (CSE)-induced lung endothelial barrier
disruption [69,70] . Cigarette smoke (CS) activates HDAC6 that results in the deacetylation of α-tubulin
and microtubule destabilization, leading to the impairment of lung endothelial barrier function and the
[70]
exacerbation of LPS- or P. aeruginosa-induced elevation in lung vascular endothelial permeability . Down-
regulation of HDAC6 by tubacin or by siRNAs to HDAC6 significantly reduces the CSE-induced elevation in
the endothelial permeability in vitro. In addition, inhibition of HDAC6 attenuates the lung inflammation and
lung edema induced by CSE in LPS- or P. aeruginosa-induced ALI animal model, indicating the involvement
[70]
of HDAC6 in the CS exacerbation of LPS- or P. aeruginosa-induced ALI .

CONCLUSION
In summary, convincing evidence support that members of the HDAC family play a critical role in the
development of ALI [Figure 1]. Manipulating the HDAC signaling pathways using multidisciplinary
approaches would provide novel therapeutic strategies for the protection of endothelial barrier function and
for the intervention of ALI in inflammatory lung diseases.