Basic fibroblast growth factor protects against influenza A virus-induced acute lung injury by recruiting neutrophils

Abstract

Influenza virus (IAV) infection is a major cause of severe respiratory illness that affects almost every country in the world. IAV infections result in respiratory illness and even acute lung injury and death, but the underlying mechanisms responsible for IAV pathogenesis have not yet been fully elucidated. In this study, the basic fibroblast growth factor 2 (FGF2) level was markedly increased in H1N1 virus-infected humans and mice. FGF2, which is predominately derived from epithelial cells, recruits and activates neutrophils via the FGFR2-PI3K-AKT-NFκB signaling pathway. FGF2 depletion or knockout exacerbated influenza-associated disease by impairing neutrophil recruitment and activation. More importantly, administration of the recombinant FGF2 protein significantly alleviated the severity of IAV-induced lung injury and promoted the survival of IAV-infected mice. Based on the results from experiments in which neutrophils were depleted and adoptively transferred, FGF2 protected mice against IAV infection by recruiting neutrophils. Thus, FGF2 plays a critical role in preventing IAV-induced lung injury, and FGF2 is a promising potential therapeutic target during IAV infection.

Fibroblast growth factor 2 decreases bleomycin‐induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation

“…Recombinant FGF2 improves recovery from myocardial ischemia, hindlimb ischemia, gastric ulcers, bone fractures, and skin wounds , and reduces liver fibrosis . In the lung, recombinant FGF2 protects from experimental emphysema, allergen‐induced airway hyperreactivity, and influenza , but has not previously been tested in models of pulmonary fibrosis. In this report, we show not only that overexpression of FGF2 reduces pulmonary fibrosis, but also that administration of intratracheal recombinant FGF2 reduces bleomycin‐induced mortality and pulmonary fibrosis.…”

Intussusceptive angiogenesis in Covid-19: hypothesis on the significance and focus on the possible role of FGF2

“…Middle East respiratory syndrome coronavirus (MERS-CoV) induces a strong apoptotic response in lung cells through upregulation of the FGF2 expression, and apoptosis seems crucial for completion of the highly lytic MERS-CoV replication cycle [18]. In influenza A(H1N1) infection, FGF2 resulted instead protective against acute lung injury, and FGF2 depletion or knockout-mice showed significantly decreased survival rates and significantly increased wet-to-dry ratios of the lung tissue [19]. Massive interstitial edema and much higher weight were indeed reported in lungs from patients who died from influenza (where the FGF2-upregulation was not detected) rather than from Covid-19 [14].…”

Respiratory Epithelial Cells as Master Communicators during Viral Infections

“…Additional cytokines contribute to neutrophil recruitment and activation, including basic fibroblast growth factor 2 (FGF2). In mice, bronchial and alveolar epithelial cells are responsible for the majority of FGF2 production induced by IAV infection [78]. Furthermore, depletion of FGF2 in infected mice increases the severity of disease [78].…”

“…In mice, bronchial and alveolar epithelial cells are responsible for the majority of FGF2 production induced by IAV infection [78]. Furthermore, depletion of FGF2 in infected mice increases the severity of disease [78]. The primary role of FGF2 in this system is to promote neutrophil chemotaxis and activation, which is needed for survival [78].…”

“…Furthermore, depletion of FGF2 in infected mice increases the severity of disease [78]. The primary role of FGF2 in this system is to promote neutrophil chemotaxis and activation, which is needed for survival [78]. While FGF2 has many functions that could contribute to protection, disease severity was reduced when neutrophil recruitment to the lungs of FGF2 deficient animals was restored.…”