Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice.

Clark, Jean C.; Wert, Susan E.; Bachurski, Cindy J.; Stahlman, Mildred T.; Stripp, Barry R.; Weaver, Timothy E.; Whitsett, Jeffrey A.

doi:10.1073/pnas.92.17.7794

Cited by 603 publications

(452 citation statements)

References 23 publications

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“…The lack of staining for mature SP-B in lungs from SP-C-TGF-␤1 mice at E18.5 further confirms the inhibitory role of TGF-␤1 on the cytodifferentiation of the alveolar Type II cells. In addition, the lack of mature SP-B may cause neonatal lethality in the TGF-␤1 mice since the targeted disruption of SP-B in mice led to respiratory failure immediately after birth (Clark et al, 1995). Type II cells in TGF-␤1 transgenic mice lacked lamellar bodies, consistent with the absence of SP-B (Clark et al, 1995).…”

Section: Discussionmentioning

confidence: 96%

“…In addition, the lack of mature SP-B may cause neonatal lethality in the TGF-␤1 mice since the targeted disruption of SP-B in mice led to respiratory failure immediately after birth (Clark et al, 1995). Type II cells in TGF-␤1 transgenic mice lacked lamellar bodies, consistent with the absence of SP-B (Clark et al, 1995). In normal mouse lung, expression of SP-C, SP-B, and CCSP genes are regulated by transcription factors TTF-1 and HNF-3␤.…”

Section: Discussionmentioning

confidence: 99%

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TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

Zeng

Gray

Stahlman

et al. 2001

Developmental Dynamics

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Members of the transforming growth factor ␤ (TGF-␤) family of polypeptides have been implicated in morphogenesis and differentiation in numerous tissues, including the lung. In order to further define effects of TGF-␤ signaling in lung morphogenesis, a constitutively active form of TGF-␤1 was expressed in respiratory epithelial cells of the fetal mouse lung in vivo. Expression of TGF-␤1 arrested lung morphogenesis in the pseudoglandular stage of development, inhibiting synthesis of differentiation-dependent proteins, SP-B, SP-C, and CCSP, and maintaining embryonic patterns of staining for thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear factor-3␤ (HNF-3␤). The pulmonary mesenchyme was thickened and vascular density was increased by TGF-␤1. TGF-␤1 decreased expression of vascular endothelial growth factor-A (VEGF-A) mRNA and protein, and the abundance of Flk-1 mRNA in the lung mesenchyme. Distribution of platelet-endothelial cell adhesion molecule (PECAM)-1, a marker of pulmonary blood vessels, was altered, and ultrastructural studies demonstrated that TGF-␤1 inhibited vascular development in the fetal lung. TGF-␤1 perturbed both epithelial cell differentiation and formation of the pulmonary vasculature, supporting the concept that precise control of signaling via the TGF-␤ receptor pathway is critical for normal lung morphogenesis.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

Zeng

Gray

Stahlman

et al. 2001

Developmental Dynamics

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“…Pulmonary surfactant is essential for normal lung function and provides several functions related to local airway conditions, such as enhancement of mucocilliary clearance, improvement of airway stability, encoating, deposition and retention of inhaled substances and particles as well as interaction with infectious agents. We focused our attention on surfactant protein B, because SP-B is necessary for the formation of the active surface film, it is essential for life (Clark et al, 1995) and an association of SP-B variants with acute respiratory failure in COPD was demonstrated (Seifart et al, 2002). Moreover, there is an association of reduced levels of SP-B observed in heterozygous SP-B knockout mice (7/+) with lung physiological abnormalities, decreased lung compliance and increased residual lung volume (Clark et al, 1997), as well as high susceptibility to oxidative lung injury (Tokieda et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Surfactant protein B knock out mice show disruption of surfactant film and function and die from respiratory failure (Clark et al, 1995(Clark et al, , 1997. Furthermore, these mice are more susceptible to oxidative lung injury (Tokieda et al, 1999).…”

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confidence: 99%

Surfactant protein B gene variations enhance susceptibility to squamous cell carcinoma of the lung in German patients

Seifart

Plagens

et al. 2002

Br J Cancer

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Genetic factors are thought to influence the risk for lung cancer. Since pulmonary surfactant mediates the response to inhaled carcinogenic substances, candidate genes may be among those coding for pulmonary surfactant proteins. In the present matched case -control study a polymorphism within intron 4 of the gene coding for surfactant specific protein B was analysed in 357 individuals. They were divided into 117 patients with lung cancer (40 patients with small cell lung cancer, 77 patients with non small cell lung cancer), matched controls and 123 healthy individuals. Surfactant protein B gene variants were analysed using specific PCR and cloned surfactant protein B sequences as controls. The frequency of the intron 4 variation was similar in both control groups (13.0% and 9.4%), whereas it was increased in the small cell lung cancer group (17.5%) and the non small cell lung cancer group (16.9%). The gene variation was found significantly more frequently in patients with squamous cell carcinoma (25.0%, P=0.016, odds ratio=3.2, 95%CI=1.24 -8.28) than in the controls. These results indicate an association of the surfactant protein B intron 4 variants and/or its flanking loci with mechanisms that may enhance lung cancer susceptibility, especially to squamous cell carcinoma of the lung.

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“…Clinical trials have found that artificial surfactants which include SP-B and SP-C are much more efficacious than protein-free surfactant preparations (10). SP-B fulfils a crucial role since hereditary SP-B deficiency is lethal in humans (11) and in SP-B knockout mice (12), while antibodies against SP-B cause RDS in ViVo (13). SP-C deficiency is not lethal at birth (14) but is associated with familial interstitial lung disease (15), and its absence modifies the biophysical properties of monolayers (14).…”

mentioning

confidence: 99%

NMR Structures of the C-Terminal Segment of Surfactant Protein B in Detergent Micelles and Hexafluoro-2-propanol

et al. 2004

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Although the membrane-associated surfactant protein B (SP-B) is an essential component of lung surfactant, which is itself essential for life, the molecular basis for its activity is not understood. SP-B's biophysical functions can be partially mimicked by subfragments of the protein, including the C-terminus. We have used NMR to determine the structure of a C-terminal fragment of human SP-B that includes residues 63-78. Structure determination was performed both in the fluorinated alcohol hexafluoro-2-propanol (HFIP) and in sodium dodecyl sulfate (SDS) micelles. In both solvents, residues 68-78 take on an amphipathic helical structure, in agreement with predictions made by comparison to homologous saposin family proteins. In HFIP, the five N-terminal residues of the peptide are largely unstructured, while in SDS micelles, these residues take on a well-defined compact conformation. Differences in helical residue side chain positioning between the two solvents were also found, with better agreement between the structures for the hydrophobic face than the hydrophilic face. A paramagnetic probe was used to investigate the position of the peptide within the SDS micelles and indicated that the peptide is located at the water interface with the hydrophobic face of the helix oriented inward, the hydrophilic face of the helix oriented outward, and the N-terminal residues even farther from the micelle center than those on the hydrophilic face of the R-helix. Interactions of basic residues of SP-B with anionic lipid headgroups are known to have an impact on function, and these studies demonstrate structural ramifications of such interactions via the differences observed between the peptide structures determined in HFIP and SDS.

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Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice.

Cited by 603 publications

References 23 publications

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

TGF‐β1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo

Surfactant protein B gene variations enhance susceptibility to squamous cell carcinoma of the lung in German patients

NMR Structures of the C-Terminal Segment of Surfactant Protein B in Detergent Micelles and Hexafluoro-2-propanol

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