Hemin Attenuated LPS-Induced Acute Lung Injury in Mice via Protecting Pulmonary Epithelial Barrier and Regulating Ho-1/Nlrp3-Mediated Pyroptosis

Abstract

Pulmonary epithelial barrier injury contributes to acute lung injury, accelerating exudate formation, and resulting alveolar edema. Heme oxygenase-1 (HO-1) plays an important role in ameliorating the pathological symptoms of acute lung injury (ALI). Using an ALI mouse model induced by LPS inhalation, the present study explored the potential molecular regulatory effect of hemin (a potent HO-1 inducer) against ALI epithelial damage. Lipopolysaccharide challenge triggered dysfunction of the alveolar epithelial barrier, impaired tight junctions, and disrupted alveoli fluid clearance, while these pathological changes were effectively reversed by hemin treatment. Furthermore, HO-1 elevation inhibited the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome and oxidative stress in alveolar epithelia, leading to the suppression of inflammatory responses and epithelial pyroptosis, as indicated by the decreased levels of NLRP3 and apoptosis-associated speck-like protein containing a CARD domain (ASC), repressed cleavage of caspase-1 and gasdermin D, and reduced expression levels of inflammatory cytokine IL-1β. In contrast, protoporphyrin IX zinc (II) (ZnPP, an HO-1 inhibitor) treatment had no protective effect on LPS inhalation-induced ALI in mice. In summary, HO-1 induction serves a critical role in maintaining airway epithelium homeostasis through the inhibition of NLRP3/ASC/caspase-1–mediated pyroptosis and inflammation in the occurrence of ALI.

The Pharmacological Effect of Hemin in Inflammatory-Related Diseases: A Systematic Review

“…ALI is normally caused by several pathological conditions, namely sepsis, pneumonia, multiple traumas, pulmonary contusion, or aspiration of dangerous gas [51]. Regarding its pathogenesis, ALI is characterized by neutrophil infiltration, accumulation of inflammatory mediators, and hyaline membrane formation [31,51,81].…”

“…ALI is normally caused by several pathological conditions, namely sepsis, pneumonia, multiple traumas, pulmonary contusion, or aspiration of dangerous gas [51]. Regarding its pathogenesis, ALI is characterized by neutrophil infiltration, accumulation of inflammatory mediators, and hyaline membrane formation [31,51,81]. This disorder is recognized as a major concern worldwide since it presents a high rate of mortality and the underlying mechanisms are not fully understood yet [31,51].…”

“…Regarding its pathogenesis, ALI is characterized by neutrophil infiltration, accumulation of inflammatory mediators, and hyaline membrane formation [31,51,81]. This disorder is recognized as a major concern worldwide since it presents a high rate of mortality and the underlying mechanisms are not fully understood yet [31,51]. The treatment with hemin showed significant anti-inflammatory (e.g., reduction in NF-kB, caspase-1, IL-1β, -6, and TNF-α) and antioxidant (e.g., reduction in MDA, MPO, and reactive oxygen species, as well and the increase in SOD) effects.…”

“…The treatment with hemin showed significant anti-inflammatory (e.g., reduction in NF-kB, caspase-1, IL-1β, -6, and TNF-α) and antioxidant (e.g., reduction in MDA, MPO, and reactive oxygen species, as well and the increase in SOD) effects. In addition, hemin was also capable of reducing the microscopical abnormalities related to the ALI induction and, consequently, the mortality rate [31,51,52].…”

Interfering Hsa_circ_0001226 Mitigates LPS-Induced Beas-2b Cell Injury by Regulating Mir-940/Tgfbr2 Pathway

“…Because of the high morbidity and mortality, it has become a major burden of public health worldwide (2). Studies have shown that acute lung injury (ALI) is the most common complication of sepsis (3,4), and about 25% to 50% of sepsis patients may occur ALI, which is the main cause of ALI (5)(6)(7). Sepsis-associated ALI (SA-ALI) is characterized by pulmonary edema and inflammatory response (8).…”