FGF signaling is required for pulmonary homeostasis following hyperoxia

Abstract

To assess the role of fibroblast growth factor (FGF) signaling in pulmonary function in the postnatal period, we generated transgenic mice in which a soluble FGF receptor (FGFR-HFc) was conditionally expressed in respiratory epithelial cells of the mouse lung, thereby inhibiting FGF activity. Although FGFR-HFc did not alter postnatal lung morphogenesis, male FGFR-HFc transgenic mice were more susceptible to hyperoxia and failed to recover when ambient oxygen concentrations were normalized. Inflammation, alveolar-capillary leak, and mortality were increased following exposure to 95% FI O 2 . Expression of surfactant protein (SP)-A and SP-B were significantly decreased in association with decreased immunostaining for thyroid transcription factor-1. FGF signaling is required for maintenance of surfactant homeostasis and lung function during hyperoxia in vivo, mediated, at least in part, by its role in the maintenance of SP-B expression. fibroblast growth factor; lung injury; surfactant protein; thyroid transcription factor-1 INHALED OXYGEN AND MECHANICAL ventilation remain the mainstay of respiratory therapy for acute respiratory distress. Despite the utility of oxygen in the maintenance of arterial oxygenation, oxygen is toxic, causing injury to both epithelial and vascular compartments of the lung. Exposure of adult mammals to 95-100% oxygen generally results in respiratory compromise and death within several days of continuous exposure (34). The lung responds to hyperoxia by enhancing the expression of cytoprotective proteins including antioxidants, surfactant proteins, and DNA repair enzymes (24,25,45). Although endotoxin, various cytokines, and polypeptide hormones, including IL-11, IL-6, EGF, and FGF-7 enhance cytoprotection of the lung during hyperoxia (4,5,30,37,(42)(43)(44), endogenous factors critical for survival and repair of the lung during oxygen exposure are not known.Intratracheal FGF-7 decreased lung injury and enhanced survival during acute lung injury caused by oxygen, acid instillation, and infection, presumably by interacting with FGF receptors on target cells. The protective effects of FGF required pretreatment of the animals before exposure to oxygen (26,46). It is less clear whether oxygen injury stimulates endogenous FGF receptor signaling to maintain pulmonary homeostasis during oxygen injury. In previous studies, transgenic mice were generated in which FGF receptor signaling was inhibited by expression of a dominant-negative soluble FGF receptor (FGFR-HFc) that was secreted by respiratory epithelial cells of the peripheral lung. Although expression of FGFR-HFc in epithelial cells of the embryonic lung blocked peripheral lung formation, its expression in the postnatal period did not alter lung morphogenesis or postnatal survival (16), thereby generating a model in which FGF signaling could be inhibited in the adult. To determine whether FGF signaling influences physiological processes in the postnatal lung, we assessed the effects of FGF receptor inhibition on pulmonary responses to hypero...

Control Mechanisms of Lung Alveolar Development and Their Disorders in Bronchopulmonary Dysplasia

“…FGF7 has also been shown to prevent lung epithelial injury induced by different forms of aggressions, including oxidative stress (66 -68), mechanical ventilation (69), and infection (70), which emphasizes its key regulatory role for the alveolar epithelial compartment. Consistently, transgenesis of a soluble FGF receptor that bound FGF7 rendered mice more susceptible to hyperoxia (71). However, FGF7 failed to protect against hyperoxic inhibition of postnatal alveolar formation and early pulmonary fibrosis in newborn rats (67).…”

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

“…Pro-surfactant protein (SP) C (or Sftpc)-positive type II AECs are required for surfactant production, and also serve as local progenitor cells that differentiate to type I epithelial cells after distal lung injury (43,44). Furthermore, inadequate recovery of SPC 1 AECs in mice with inhibition of FGF signaling in response to hyperoxiainduced lung injury causes respiratory failure and death (45). We therefore hypothesized that the mortality observed in Fgf2 2/2 mice after bleomycin represented a failure to repair damaged epithelium.…”

“…Inhibition of FGFR2b ligands in vivo worsens hyperoxic lung injury (45). The requirement of these specific ligands for bleomycin-induced lung injury, however, has not been demonstrated in vivo.…”

Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair

“…The line was previously used in the context of naphthalene and hyperoxia lung injury to demonstrate the critical role of Fgfr2b ligands in the lung repair process (12,13,39). In addition, this line was also used to define the role of Fgfr2b ligands during early lung embryonic and late lung development (12), limb development (6), postnatal mammary gland development (29), incisor homeostasis (28), and gut homeostasis (1).…”

“…The impact of trapping Fgfr2b ligands during lung injury has been previously reported. Induction of soluble Fgfr2b under the SpC-rtTA/ϩ promoter in adult mice subjected to hyperoxia injury led to abnormal expression of surfactant during injury, which contributed to increased lethality (13). A Fig.…”