Intratracheal Administration of Recombinant Human Keratinocyte Growth Factor Promotes Alveolar Epithelial Cell Proliferation during Compensatory Lung Growth in Rat

Abstract

Keratinocyte growth factor (KGF) is considered to be one of the most important mitogens for lung epithelial cells. The objectives of this study were to confirm the effectiveness of intratracheal injection of recombinant human KGF (rhKGF) during compensatory lung growth and to optimize the instillation protocol. Here, trilobectomy in adult rat was performed, followed by intratracheal rhKGF instillation with low (0.4 mg/kg) and high (4 mg/kg) doses at various time-points. The proliferation of alveolar cells was assessed by the immunostaining for proliferating cell nuclear antigen (PCNA) in the residual lung. We also investigated other immunohistochemical parameters such as KGF, KGF receptor and surfactant protein A as well as terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Consequently, intratracheal single injection of rhKGF in high dose group significantly increased PCNA labeling index (LI) of alveolar cells in the remaining lung. Surprisingly, there was no difference in PCNA LI between low and high doses of rhKGF with daily injection, and PCNA LI reached a plateau level with 2 days-consecutive administration (about 60%). Our results indicate that even at low dose, daily intratracheal injection is effective to maintain high proliferative states during the early phase of compensatory lung growth.

AhR-E2F1-KGFR signaling is involved in KGF-induced intestinal epithelial cell proliferation

“…Villus height, crypt depth, intestinal wet weight, RNA levels and protein expression analysis also indicated that AhR knockout mice presented compromised KGF-induced intestinal changes. Previous studies have reported that AhR, as a conserved nuclear transcription protein, serves an important role in cell proliferation ( 24 – 27 ). Interestingly, other work in the field found that AhR regulates the expression of receptors that meditated cell survival and growth.…”

Keratinocyte Growth Factor Gene Electroporation into Skeletal Muscle as a Novel Gene Therapeutic Approach for Elastase-Induced Pulmonary Emphysema in Mice

“…Yildirim et al reported that intra-tracheal multicycle application of 10 mg KGF protein/kg body weight was necessary to achieve a maximal proliferative response in alveolar type II epithelial cells in the elastase-induced emphysema model [ 46 ]. On the other hand, Furukawa et al reported that the repeated administration of a low dose of KGF (0.4 mg/kg) gave the same effect as that of administration of a high dose (4 mg/kg) [ 12 ]. Currently, the optimal treatment threshold for the gene transfer method using electroporation in this animal model is unclear, because of differences in the route of administration and the absorption efficiency in the different studies.…”

“…We also previously showed that administration of a KGF-expressing plasmid using electroporation significantly enhanced compensatory lung growth [ 24 ]. Moreover, exogenous KGF was shown to augment lung epithelial cell proliferation and to decrease the average airspace distance [ 12 ]. In terms of COPD treatment , we therefore considered that KGF, which is synthesized in different tissues far from the lung, may play a beneficial role in lung repair or preventing progression of emphysema.…”