Could Heme Oxygenase-1 Be a New Target for Therapeutic Intervention in Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome?

Abstract

Malaria is a serious disease and was responsible for 429,000 deaths in 2015. Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the main clinical complications of severe malaria; it is characterized by a high mortality rate and can even occur after antimalarial treatment when parasitemia is not detected. Rodent models of ALI/ARDS show similar clinical signs as in humans when the rodents are infected with murine Plasmodium. In these models, it was shown that the induction of the enzyme heme oxygenase 1 (HO-1) is protective against severe malaria complications, including cerebral malaria and ALI/ARDS. Increased lung endothelial permeability and upregulation of VEGF and other pro-inflammatory cytokines were found to be associated with malaria-associated ALI/ARDS (MA-ALI/ARDS), and both were reduced after HO-1 induction. Additionally, mice were protected against MA-ALI/ARDS after treatment with carbon monoxide- releasing molecules or with carbon monoxide, which is also released by the HO-1 activity. However, high HO-1 levels in inflammatory cells were associated with the respiratory burst of neutrophils and with an intensification of inflammation during episodes of severe malaria in humans. Here, we review the main aspects of HO-1 in malaria and ALI/ARDS, presenting the dual role of HO-1 and possibilities for therapeutic intervention by modulating this important enzyme.

MicroRNA‐155 inhibits dengue virus replication by inducing heme oxygenase‐1‐mediated antiviral interferon responses

“…Meanwhile, HO‐1 is a well‐recognized modulator of the immune response and inflammation . In humans, HO‐1 deficiency is associated with an increased pro‐inflammatory state in endothelial cell injury . Mice lacking HO‐1 showed enhanced sensitivity to LPS‐induced toxemia .…”

Lutzomyia longipalpis Saliva Induces Heme Oxygenase-1 Expression at Bite Sites

“…HO-1 is thought to be an intracellular enzyme ( 27 ), and its detection in plasma would indicate substantial tissue damage. In this scenario, the release of HO-1 occurs after cellular lysis during robust inflammation associated with infectious diseases such as VL ( 21 , 28 , 29 ), tuberculosis ( 30 ) and malaria ( 31 , 32 ). For sand fly bite-induced HO-1 expression in the skin, our data demonstrates that it is triggered in resident skin macrophages by saliva and as such could play a critical role in the early establishment of Leishmania infection.…”

Serum heme oxygenase-1 measurement is useful for evaluating disease activity and outcomes in patients with acute respiratory distress syndrome and acute exacerbation of interstitial lung disease

“…In the present study, ARDS patients had signi cantly higher serum HO-1 and CRP levels at baseline compared with AE-ILD patients and serum HO-1 had positive correlation with serum LDH. These results indicate that ARDS patients had a stronger degree of systemic in ammatory response, pulmonary epithelial cell damage and endothelial cell damage with the consequent increase of vascular permeability re ecting oxidative/nitrosative stress response than AE-ILD patients (32)(33)(34). Though similar with HO-1, SODs, catalase, and GPx had been described as the endogenous antioxidants, HO-1 characterized as stress response protein with relatively small-molecular weight (32 kDa, much smaller than KL-6 (5000 kDa)), rapid response against stimuli, and various physiological activities including the antiapoptotic, anti-in ammatory, vasodilatory, anticoagulant, antioxidant, and antiproliferative reactions caused by HO-1 metabolites (7,(15)(16)(17).…”