Suppression of inflammatory cell trafficking and alveolar simplification by the heme oxygenase-1 product carbon monoxide

Abstract

, a lung disease of prematurely born infants, is characterized in part by arrested development of pulmonary alveolae. We hypothesized that heme oxygenase (HO-1) and its byproduct carbon monoxide (CO), which are thought to be cytoprotective against redox stress, mitigate lung injury and alveolar simplification in hyperoxia-exposed neonatal mice, a model of BPD. Three-day-old C57BL/6J mice were exposed to air or hyperoxia (FI O 2 , 75%) in the presence or absence of inhaled CO (250 ppm for 1 h twice daily) for 21 days. Hyperoxic exposure increased mean linear intercept, a measure of alveolar simplification, whereas CO treatment attenuated hypoalveolarization, yielding a normal-appearing lung. Conversely, HO-1-null mice showed exaggerated hyperoxia-induced hypoalveolarization. CO also inhibited hyperoxia-induced pulmonary accumulation of F4/80 ϩ , CD11c ϩ , and CD11b ϩ monocytes and Gr-1 ϩ neutrophils. Furthermore, CO attenuated lung mRNA and protein expression of proinflammatory cytokines, including the monocyte chemoattractant CCL2 in vivo, and decreased hyperoxia-induced type I alveolar epithelial cell CCL2 production in vitro. Hyperoxia-exposed CCL2-null mice, like COtreated mice, showed attenuated alveolar simplification and lung infiltration of CD11b ϩ monocytes, consistent with the notion that CO blocks lung epithelial cell cytokine production. We conclude that, in hyperoxia-exposed neonatal mice, inhalation of CO suppresses inflammation and alveolar simplification.

Obesity-induced remodeling of the adipose tissue elastin network is independent of the metalloelastase MMP-12

“…2E) The mean linear intercept (MLI) method was utilized to quantify reticulation (increased branching is associated with a decrease in MLI). 21,22 This demonstrated a significant increase in elastin branching in eWAT compared to iWAT and an increase in branching with HFD feeding (decrease in MLI) (Fig. 2F).…”

Role of the Nrf2/HO-1 axis in bronchopulmonary dysplasia and hyperoxic lung injuries

“…However, in this model HO-1 overexpression was not able to restore normal alveolar growth. Indeed, newborn mice exposed to hyperoxia and CO inhaled (250 ppm for 1 h two times per day) for 21 days showed an important role in restoring normal MLI (a parameter related to regular lung morphometry) and hypoalveolarization attenuation [85], whereas, HO −/− mice showed magnified hyperoxia-induced alveolarization dysfunctions. Kawamura et al [86] have obtained interesting results by studying the effect of gaseous hydrogen (H 2 ) -an acknowledged ROS scavenger, antioxidant, and anti-inflammatory gasotransmitter on Nrf2 pathway [87].…”

Heme Oxygenase-1-Expressing Dendritic Cells Promote Foxp3+ Regulatory T Cell Differentiation and Induce Less Severe Airway Inflammation in Murine Models

“…HO-1 degrades heme into free divalent iron, carbon monoxide and biliverdin, while these metabolites are known for the cytoprotective and anti-inflammatory effects in various disease contexts, including allogenic graft transplantation [1], pregnancy [2], and neutrophilic airway inflammation [3]. Recent studies of HO-1 on lung inflammation and injury clearly show the cytoprotective effect against oxidative stress and lung inflammation by reducing neutrophils infiltration from bone marrow [4, 5]. Understanding the mechanism of HO-1 system in DC’s function may help to design antigen (Ag)-specific therapeutic strategy for lung diseases.…”