Abstract
Acute lung injury (ALI) afflicts approximately 200,000 patients annually and has a 40% mortality rate. The COVID-19 pandemic has massively increased the rate of ALI incidence. The pathogenesis of ALI involves tissue damage from invading microbes and, in severe cases, the overexpression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). This study aimed to develop a therapy to normalize the excess production of inflammatory cytokines and promote tissue repair in the lipopolysaccharide (LPS)-induced ALI. Based on our previous studies, we tested the insulin-like growth factor I (IGF-I) and BTP-2 therapies. IGF-I was selected, because we and others have shown that elevated inflammatory cytokines suppress the expression of growth hormone receptors in the liver, leading to a decrease in the circulating IGF-I. IGF-I is a growth factor that increases vascular protection, enhances tissue repair, and decreases pro-inflammatory cytokines. It is also required to produce anti-inflammatory 1,25-dihydroxyvitamin D. BTP-2, an inhibitor of cytosolic calcium, was used to suppress the LPS-induced increase in cytosolic calcium, which otherwise leads to an increase in proinflammatory cytokines. We showed that LPS increased the expression of the primary inflammatory mediators such as toll like receptor-4 (TLR-4), IL-1β, interleukin-17 (IL-17), TNF-α, and interferon-γ (IFN-γ), which were normalized by the IGF-I + BTP-2 dual therapy in the lungs, along with improved vascular gene expression markers. The histologic lung injury score was markedly elevated by LPS and reduced to normal by the combination therapy. In conclusion, the LPS-induced increases in inflammatory cytokines, vascular injuries, and lung injuries were all improved by IGF-I + BTP-2 combination therapy.
Highlights
The current study was undertaken to determine if insulin-like growth factor I (IGF-I), BTP-2, or IGF-I + BTP-2 therapy would ameliorate the lung damage in a mouse model of LPS-induced Acute lung injury (ALI)
Since the mice utilized in this lung study were previously evaluated for acute kidney injury [13], we provided a comparison of the therapeutic and mechanistic features of these two major organs
The overall approach for the therapeutic analysis of the IGF-I and BTP-2 therapies for LPS-induced ALI was to focus on three essential biologic processes of inflammation and repair—namely, (1) increased production of the proinflammatory cytokines, (2) impaired vascular function, and (3) improved repair
Summary
Acute lung injury (ALI) often manifests as acute respiratory failure. ALI can occur from local or systemic causes and can result from infectious or noninfectious causes [1]. Acute lung injury and acute respiratory distress syndrome (ARDS) are considered a continuum [1]. It has been estimated that ~200,000 patients are afflicted annually, with a 40% mortality rate [2]. With the pandemic of COVID-19, ALI is massively increased. ALI therapy is currently mainly supportive, new therapies are rapidly emerging [3]
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