Expression of the Insulin-Like Growth Factor System in Postpneumonectomy Lung Growth

Price, Wayne A.; Moats‐Staats, Billie M.; Sekhon, Harman S.; Chrzanowska, B; Thurlbeck, William M.; Stiles, Alan D.

doi:10.3109/01902149809099583

Cited by 10 publications

(15 citation statements)

References 27 publications

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“…It was remarkable how many of the commercial antibodies to IGF-I that we assessed lacked specificity, which may account for some of the discrepancies evident in the lung IGF literature (29,35). Differences in antibody specificity could also account for our finding of relatively stable IGF-I/IGF-R1 content after birth when others have described postnatal age-dependent variability (24).…”

Section: Discussionmentioning

confidence: 58%

“…Whether IGF-II signaling through the IGF-R1 plays a role in postnatal alveologenesis remains an open question, although it has been suggested, at least in mice (2), that IGF-II plays little or no role in postnatal growth. The IGF-I/IGF-R1 pathway has been studied during the compensatory alveologenesis that occurs following pneumonectomy, but with discrepant results (29,35). The IGF-R2 is only indirectly involved in positive growth regulation, through targeting bound IGF-II to lysosomes for degradation (5).…”

mentioning

confidence: 98%

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The IGF-I/IGF-R1 pathway regulates postnatal lung growth and is a nonspecific regulator of alveologenesis in the neonatal rat

Masood

Man

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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IGF-I, IGF-II, and the IGF-I receptor are widely distributed throughout the neonatal rat lung on days 4, 7, 10, and 14 of life, with a similar abundance at each of these time points. Injection of 20 μg/g of a truncated soluble IGF-I receptor on days 2 and 5 of life, to decoy ligand away from the endogenous IGF-I receptor, reduced lung weight and lung-to-body weight ratio, reduced lung tissue fraction, and impaired alveolar formation, as assessed by secondary crest formation and mean linear intercepts on day 7 of life. Lung procollagen I content and elastin fiber density were also reduced. Injection of 100 μg/day of neutralizing anti-IGF-I, to prevent IGF-I from binding to the IGF-I receptor, on days 3, 4, and 5 of life reduced tissue fraction and elastin fiber density and impaired alveolar formation on day 6 of life. Both interventions reduced total lung cell and secondary crest cell DNA synthesis and small vessel counts per unit area, but these effects were lost after normalization to the reduced tissue fraction. These findings are consistent with a role for IGF-I binding to the IGF-I receptor in postnatal lung growth and on alveologenesis through a nonspecific positive effect on DNA synthesis. Injection of 100 μg/day of neutralizing anti-IGF-II, to prevent IGF-II from binding to the IGF-I receptor, on days 3, 4, and 5 of life had no effect on total lung cell DNA synthesis per unit area on day 6 of life, and a role for IGF-II in postnatal alveologenesis was not further pursued.

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Section: Discussionmentioning

confidence: 58%

mentioning

confidence: 98%

The IGF-I/IGF-R1 pathway regulates postnatal lung growth and is a nonspecific regulator of alveologenesis in the neonatal rat

Masood

Man

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…A pharmacological intervention with a truncated PDGF-R␤/Fc soluble receptor has allowed us to demonstrate a causal relationship between PDGF-BB and postpneumonectomy compensatory DNA synthesis. This observation also brings into question the assumption that no increase in normalized growth factor mRNA or protein, after pneumonectomy, automatically excludes a role in compensatory growth, as reported for IGF-I (20).…”

mentioning

confidence: 72%

“…IGF-I does not appear to be an endocrine growth factor after pneumonectomy in rabbits (18). Altered expression of IGF-I has been both reported to play (19), and not play (20), a role in postpneumonectomy lung growth in rats. An increase in IGF-I has been reported after pneumonectomy in lambs (21).…”

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confidence: 99%

A Role for Platelet-Derived Growth Factor-BB in Rat Postpneumonectomy Compensatory Lung Growth

et al. 2002

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Unilateral pneumonectomy leads to compensatory growth in the residual lung, the mediators of which are largely unknown. We hypothesized, based on its other known roles in lung cell growth, that platelet-derived growth factor (PDGF)-BB would be an essential mediator of postpneumonectomy compensatory lung growth. Left-sided pneumonectomies were performed on 21-dold rats, for comparison with sham-operated or unoperated control animals. Body weights were not different between groups. Right lung weights and DNA content were significantly increased (p Ͻ 0.05), compared with controls, by 10 d after pneumonectomy. The rate of DNA synthesis was maximal on d 5 postpneumonectomy. Total right lung PDGF-B mRNA and PDGF-BB protein increased after pneumonectomy, but were apparently tightly regulated, relative to total right lung ␤-actin mRNA and protein content, respectively. However, PDGF-BB expression after pneumonectomy was apparently not purely constitutive, in that daily i.p. injections of a truncated soluble PDGF ␤-receptor both reduced activation of the native PDGF ␤-receptor, and attenuated increased lung DNA synthesis on d 3 after pneumonectomy. These findings are consistent with a critical role for PDGF-BB in postpneumonectomy lung growth. Children and adolescents subjected to a unilateral pneumonectomy develop a varying degree of compensatory growth in the contralateral lung (1). Extensive animal studies have enhanced our understanding of this process (2-7). The degree of compensatory growth achieved is reduced with age, but, if lung tissue is removed sufficiently early in life, there is an almost complete restitution of air space, capillary and tissue volumes, and alveolar and capillary surface areas to normal (8, 9). Physiologic, pathophysiological, and morphologic studies suggest that, at least in small animal species, this compensatory growth occurs within the first 2 wk after surgery (5, 6, 10). Cellular hyperplasia is evident during compensatory lung growth (10, 11), with increased mitotic indices of parenchymal cells, total DNA, and DNA synthesis (as measured by incorporation of [ 3 H]thymidine) having been observed in rats (10 -13), mice (14), and rabbits (6).Successful postpneumonectomy lung growth is likely to require the coordinated expression of various growth factors and their receptors, directed at the different cell types within the lung (15), acting through autocrine, endocrine, juxtacrine, or paracrine pathways. Despite an extensive literature relating to experimental pneumonectomy, the mediators of compensatory growth in the residual lung tissue have not been elucidated. It has been shown that the immediate-early genes c-fos and jun-B are up-regulated very rapidly (30 min) after pneumonectomy (16). However, the downstream events that follow this early response, and mediate the proliferative response, are not clear. It has been suggested that tumor necrosis factor may be one of the hormonal factors implicated in postpneumonec-

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“…In addition, elevated serum somatomedin C was found in pregnant rats 2 and 5 days following PNX [34]. A more thorough study of IGF expression and function during post-PNX compensatory lung growth failed to demonstrate differences between the lungs of PNX and SHAM-operated animals in either IGF-1 mRNA abundance or serum IGF-1 levels [40]. These discrepancies may be attributable to differences in strain or hormonal status of the animals [40].…”

Section: Regulation Of Post-pnx Growthmentioning

confidence: 99%

Implications of post-pneumonectomy compensatory lung growth in pulmonary physiology and disease

Brown

Rannels

2001

Respir Res

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ADX = adrenalectomy; BHT = butylated hydroxytoluene; BW = body weight; GH = growth hormone; IGF = insulin-like growth factor; PNX = partial pneumonectomy; RLW = right lung weight; SHAM = sham pneumonectomy; TLW = total lung weight.Available online http://respiratory-research.com/content/2/6/340 IntroductionPartial pneumonectomy (PNX), the surgical removal of a lung lobe or lobes, substantially diminishes diffusion capacity by reducing the total number of alveoli and the associated vasculature available for gas exchange. The immediate challenge to a pneumonectomized animal is to maintain adequate gas exchange following resection of lung tissue. Physiological compensation for the loss of lung mass is achieved primarily through two mechanisms: enhancement of diffusion capacity in the remnant lung, and/or generation of new pulmonary gas exchange units.PNX elicits a number of anatomical changes within the thoracic cavity that augment the diffusion capacity of the remaining lobes. Ligation and surgical removal of one or more lobes directs the entire cardiac output into remaining lung tissue and creates an empty hemithorax that results in a shift of the mediastinum toward the vacated thoracic compartment [1,2]. In addition, increased space within the chest releases constraints on lung expansion imposed by the thoracic wall. Increased lung inflation on inspiration can then recruit alveoli that might have been incompletely ventilated prior to PNX. Likewise, increased pulmonary blood flow to the remaining tissue may contribute to tissue distension and enhance parenchymal perfusion. As a consequence of these post-surgical anatomical changes, adequate gas exchange can be re-established after PNX by exploiting the physiological reserves of diffusion capacity in the remaining lung tissue.A second adaptive response to PNX is compensatory growth of the remaining lobes. In a variety of mammalian species, PNX stimulates rapid compensatory lung growth, restoring normal mass, structure and function. Although post-PNX compensatory lung growth has been documented in rabbits [3], mice [4,5], ferrets [6,7] and dogs [8,9] AbstractIn a number of species, partial pneumonectomy initiates hormonally regulated compensatory growth of the remaining lung lobes that restores normal mass, structure and function. Compensation is qualitatively similar across species, but differs with gender, age and hormonal status. Although the biology of response is best characterized in rats, dogs have proven valuable in defining post-operative physiological adaptations. Most recently, mice were recognized to offer unique opportunities to explore the genetic basis of the response, as well as to evaluate associated detrimental effects of pathophysiological significance in animals exposed to carcinogens. The pneumonectomy model thus offers powerful insight concerning adaptive organ growth.

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Expression of the Insulin-Like Growth Factor System in Postpneumonectomy Lung Growth

Cited by 10 publications

References 27 publications

The IGF-I/IGF-R1 pathway regulates postnatal lung growth and is a nonspecific regulator of alveologenesis in the neonatal rat

The IGF-I/IGF-R1 pathway regulates postnatal lung growth and is a nonspecific regulator of alveologenesis in the neonatal rat

A Role for Platelet-Derived Growth Factor-BB in Rat Postpneumonectomy Compensatory Lung Growth

Implications of post-pneumonectomy compensatory lung growth in pulmonary physiology and disease

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