ABSTRACT
I. Introduction 317
II. SP-C Structure and Function 318
III. SP-C Gene Structure and Expression 319
IV. SP-C Transgenes Identify Regions that Specify Pulmonary
Epithelial Cell Expression 319
V. Altered Expression of SP-C and Familial ILD in Humans 322
VI. SP-C Knockout Mice as a Model of ILD 323
VII. Abnormalities in Surfactant Composition and Function with
SP-C Deficiency 325
VIII. Utility of Current SP-C Mouse Models to Explore Pathogenic
Mechanisms and Therapy for Familial ILD 326
Acknowledgment 326
References 327
I. Introduction
Experiments that use genetically modified mice are providing new insights into
the molecular basis of pulmonary developmental disorders (neonatal surfactant
deficiency) and diseases that result from injury, environmental exposures, or
hereditary defects. Broadly speaking, such preplanned alterations can be classified
as gain-or loss-of-function. Gain-of-function is usually performed by the perma-
nent insertion of a modified DNA construct that has been microinjected into the
fertilized mouse egg. The injected DNA inserts randomly into the genome (trans-
gene) and if it is inserted into an active region of chromatin, the biological
activity of the transgene can be assessed. Transgenic mice have been used to
identify candidate promoter regions of lung-specific genes that direct tissue
and cell-specific patterns of expression. Lung-specific promoters, in turn, are
being used to direct high-level expression of effector molecules such as growth
factors, cytokines, or transcription factors to define their biological function
(1-3). Loss-of-function is usually accomplished by targeted gene inactivation
(gene targeting). Gene targeting is accomplished by homologous recombination
into the native gene of a mutated gene producing an inactive allele. Gene inacti-
vation is accomplished in pluripotent embryonic stem (ES) cells, and mice gen-
erated from the modified ES cells develop in the absence of the targeted gene
product. Functional consequence of the gene inactivation can be determined in
the resultant knockout mice and the role of the inactivated gene product inferred
(4). The goals of this chapter are to summarize how in vivo analysis of the pul-
monary surfactant protein C (SP-C) gene has been used to (1) characterize
genomic sequences that direct developmental and type II cell-specific gene
expression and (2) model interstitial lung disease (ILD) related to recently
identified familial deficiencies of SP-C.
