Primary rat adipocytes cultured in basement membrane component gels migrated and organized into large, three-dimensional, multicellular clusters. Gross morphological changes seen during this reorganization are described. The rate of cluster formation decreased with age of the rats and was stimulated by insulin in older, but not in younger rats. Echistatin, a disintegrin, partially inhibited the formation of multicellular clusters in a concentration-dependent fashion (50% inhibitory concentration approximately 10 nM). The original extracellular matrix was initially remodeled and eventually destroyed by the time large multicellular clusters were observed. This implied that one or more matrix-degrading protease(s) were being secreted. Adipocyte-conditioned medium was found to contain a divalent cation-sensitive gelatinase activity at approximately 72 and/or approximately 62 kDa. The elution profile of this activity from gelatin-Sepharose 4B was similar to matrix metalloproteinase 2 (MMP-2, a 72-kDa matrixin with a 62-kDa mature form), and the dimethyl sulfoxide eluant from these columns contained MMP-2 immunoreactivity. MMP-2 concentration and activity were greater in conditioned medium from young than from older animals; however, insulin did not affect the amount of MMP-2 in adipocyte-conditioned media. The matrixin inhibitor 1,10-phenanthroline not only blocked gelatinase activity in zymograms but also prevented extracellular matrix remodeling and destruction, as well as adipocyte migration and the formation of cell-cell contacts in adipocyte cultures. These observations are consistent with the hypothesis that the matrixin MMP-2 is secreted by adipocytes. Whereas matrixin activity alone may not be sufficient for the formation of multicellular clusters, the data indicate that it may have a requisite role in this process.

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.

No abstract