HIF-1α: a bridge connecting sepsis and acute respiratory distress syndrome

Abstract

Sepsis is a life-threatening condition marked by an abnormal host response to infection that can result in organ dysfunction, making it recognized as one of the primary causes of acute respiratory distress syndrome (ARDS). The pathophysiology of sepsis involves a cascade of events, including heightened pulmonary capillary permeability, dysfunction of alveolar epithelial cells, and the infiltration of inflammatory cells, such as neutrophils, macrophages, monocytes, and lymphocytes. The presence of these inflammatory cells triggers capillary leakages, alveolar epithelial damage, and the accumulation of fluid within the alveolar spaces, leading to compromised gas exchange, acute respiratory failure, and the progression to ARDS. In this complex scenario, Hypoxia-Inducible Factor-1α (HIF-1α) emerges as a pivotal player in maintaining cellular oxygen homeostasis and responding to hypoxia and inflammatory stimuli. This narrative review delves into the intricate molecular and biological characteristics of HIF-1α, elucidating its regulatory role within the context of sepsis and ARDS. By exploring the therapeutic potential of targeting HIF-1α, this review seeks to offer valuable insights into the underlying mechanisms linking sepsis to ARDS. Ultimately, this exploration of HIF-1α seeks to enhance our comprehension of sepsis pathogenesis, identify novel therapeutic avenues, and lay a strong theoretical groundwork for future clinical interventions.

Keywords: Acute respiratory distress syndrome; Critical care; HIF-1α; Hypoxia; Molecular medicine; Sepsis.

Fig. 1

Regulation of HIF-1α: oxygen-dependent and inflammation-related pathways. a Oxygen-dependent pathway regulates HIF-1α levels. Under normoxic conditions, prolyl hydroxylases (PHDs) and factor inhibiting HIF (FIH) hydroxylate specific proline and asparagine residues of HIF-1α. This modification marks HIF-1α for degradation via a chain of biological processes. However, under hypoxic conditions, it inhibits the activity of PHDs and FIH, stabilizing HIF-1α. This stabilized form translocates to the nucleus, where it dimerizes with HIF-1β to form the HIF complex, which then binds to HREs in the regulatory regions of target genes. b Nuclear factor-κB (NF-κB) pathway regulates HIF-1α levels. Activation of inhibitor of kappa B kinase (IKK) leads to phosphorylation and subsequent ubiquitination (Ub) of IκB (Inhibitor of NF-κB) protein, releasing the NF-κB dimer. The free NF-κB translocates to the nucleus, binds DNA, and promotes the transcription of genes that regulate HIF-1α. c Phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway regulates HIF-1α levels. Factor stimulation activates PI3K, generating inositol triphosphate (PIP3), a second messenger that activates Akt. Akt subsequently activates the mammalian Target of Rapamycin (mTOR), which contributes to HIF-1α regulation. d Signal transducer and activator of transcription 3 (STAT3) pathway regulates HIF-1α levels. Cytokine-mediated activation of JAK phosphorylates STAT3. The phosphorylated STAT3 forms dimers that compete with the von Hippel–Lindau (pVHL) for binding to HIF-1α, thereby influencing its levels. List of abbreviations: HIF-1α: Hypoxia Inducible Factor-1, PHDs: Prolyl hydroxylases, FIH: Factor inhibiting HIF, HREs: Hypoxia response elements, NF-κB: Nuclear Factor-κB, IKK: Inhibitor of kappa B kinase, Ub: Ubiquitination, IκB: Inhibitor of NF-κB, DNA: Deoxyribonucleic acid, PI3K/Akt: Phosphatidylinositol 3-kinase/protein kinase B, PIP3: Inositol triphosphate, mTOR: Mammalian target of rapamycin, STAT3: Signal transducer and activator of transcription 3, JAK: Janus kinase, pVHL: von Hippel–Lindau.

Fig. 2

Multifaceted protective mechanisms of HIF-1α in pulmonary epithelial cells. HIF-1α promotes vascular repair, egression of inflammatory injury, and alveolar type II epithelial cell proliferation by regulating the Foxm1 signaling pathway. HIF-1α promotes reduction of lung injury and anti-apoptotic protection in lung epithelial cells by regulating the Fas/FasL. HIF-1α alleviates alveolar epithelial cell injury by enhancing glycolytic activity and compensating for mitochondrial dysfunction. List of abbreviations: HIF-1α: Hypoxia Inducible Factor-1

Fig. 3

Regulatory Role of HIF-1α on Key Inflammatory Factors. HIF-1α upregulates IL-1β and IL-6 through the NF-κB signaling pathway; HIF-1α binds to the IL-10 and IFN-γ promoters at the HRE to upregulate IL-10 and IFN-γ; Inhibition of IL-8 expression by HIF-1α is associated with downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) By activation of retinoid-related orphan nuclear receptor γt (RORγt), or in conjunction with RORγt, HIF-1α upregulates IL-17 through p300 recruitment and histone acetylation. List of abbreviations: HIF-1α: Hypoxia Inducible Factor-1, IL-1β: Interleukin-1β, IL-6: Interleukin-6, NF-κB: Nuclear Factor-κB, IL-10: Interleukin-10, IFN-γ: Interferon-γ, HRE: Hypoxia response elements, IL-8: Interleukin-8, Nrf2: Nuclear factor erythroid 2-related factor 2, RORγt: Retinoid-related orphan nuclear receptor γt, IL-17: Interleukin-17.