Further examination of alveolar septal adaptation to left pneumonectomy in the adult lung

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Abstract

Recent data from our laboratory are presented concerning alveolar septal adaptation following 42–45% lung resection by left pneumonectomy (PNX) in adult foxhounds compared to sham-operated control animals. Results confirm our previous conclusion that compensation in the remaining lung occurs without a net growth of additional alveolar septal tissue. The major ultrastructural responses are (a) alveolar capillary distention, which recruits capillary blood volume and surface area, leading to a 30–50% increase in lung diffusing capacity estimated by morphometry, a magnitude similar to that measured by physiologic methods; (b) a selectively increased volume of type 2 alveolar epithelial cells. These data, taken together with the balanced compensatory growth of alveolar septal cells observed in adult dogs following 55–58% lung resection by right PNX, support a graded alveolar cellular response to chronic mechanical strain with the alveolar epithelial cells being activated first; as strain increases further with greater lung resection other alveolar cells also become activated leading to an overt increase in septal tissue volume. The spatial distribution of lobar mechanical strain and lobar tissue volume assessed by high resolution computed tomography was markedly non-uniform after PNX, suggesting possible non-uniform distribution of alveolar cellular response. The sequential activation of physiologic recruitment and cellular adaptation confer additive functional benefits that optimize long-term exercise performance after PNX.

Introduction

The surgical resection of one lung or pneumonectomy (PNX) is a robust experimental model that has been utilized for over 100 years to study how the respiratory system adapts to restrictive lung disease. The major advantages of this model are the imposition of a known and reproducible loss of lung units and the lack of injury to the remaining lung, enabling a rigorous assessment of the response of the remaining functioning lung units. Studies from our laboratory have systematically defined three general sources of post-PNX compensation that enhance gas exchange capacity of the remaining lung under different experimental conditions, including (a) recruitment of remaining physiologic reserves; (b) remodeling of existing lung structure; (c) new growth of additional lung tissue (Hsia, 2002, Hsia, 2004, American Thoracic Society Workshop Document, 2004, Hsia et al., 2004). In actively growing animals PNX elicits accelerated growth of alveolar septal tissue in the remaining lung that eventually normalizes gas exchange and aerobic capacity (Takeda et al., 1999). In contrast in adult animals where the regenerative potential is limited, the sources of post-PNX compensation vary depending upon the magnitude and uniformity of mechanical strain imposed on the remaining lung units. Compensatory growth of new alveolar septal tissue is evident in the adult lung following 55–58% lung resection by right PNX but not following less extensive 42–45% resection by left PNX (Hsia et al., 1993, Hsia et al., 1994a, Hsia et al., 1994b). Even in the absence of active regeneration of gas exchange tissue after left PNX, a significant (about 30%) compensatory increase in physiologic lung diffusing capacity (DLCO) develops at rest as well as during exercise and constitutes a major factor for the maintenance of a nearly normal aerobic capacity (Hsia et al., 1991). We have previously discussed how recruitment of physiologic reserves or growth of new alveolar tissue might enhance DLCO. In this article we will discuss recent experimental data that address how ultrastructural remodeling of alveolar septa contribute to post-PNX functional compensation.

The Webster Dictionary defines “remodel” as a transitive verb meaning “to alter the structure of”, “to make anew”, and “to change the form of”. In morphology “remodel” has been used rather loosely to denote structural alterations at each level of tissue organization in response to development, intervention, injury or disease. During both developmental and compensatory lung growth, more airways, vascular and alveolar tissue are added while the existing cells and matrix are rearranged or pruned in order to prevent architectural distortion and to preserve functional integrity of the organ. The typical developing lung undergoes progressive parenchymal involution with increased epithelial and interstitial apoptotic activity (De Paepe et al., 1999), lengthening of alveolar septa, thinning of the alveolar blood-gas diffusion barrier as well as redistribution of tissue components with maturation (Mansell et al., 1995, Willet et al., 1999).

Even in the absence of new tissue growth, on-going rearrangement of septal cells and matrix can significantly improve gas exchange efficiency. A concrete example is the response of the adult lung to the loss of 42–45% of lung mass by left PNX. Initially we studied 3 foxhounds before and about 2 years after undergoing left PNX as adults (Carlin et al., 1988, Carlin et al., 1991, Hsia et al., 1990a, Hsia et al., 1990b, Hsia et al., 1991, Hsia et al., 1992, Hsia et al., 1993). Lung function was measured at rest and during exercise pre-and post-PNX and the results were paired for comparison. At postmortem, the remaining right lung was fixed for detailed morphometric analysis of alveolar ultrastructure using established techniques. These early morphometric results (Hsia et al., 1993) were compared to the only historical reference data available at that time, which was obtained in the right lung of three normal adult mongrel dogs (Weibel et al., 1987). We reported that the remaining right lung after left PNX was 63% larger than a normal right lung with visibly enlarged alveolar airspaces and a 40% lower volume density of septal tissue per unit of lung volume. The mean arithmetic and harmonic thickness of septal tissue was lower, but there was no post-PNX increase in the absolute volumes of alveolar septal tissue and cell components or in alveolar-capillary surface areas. We concluded that the major structural adaptation in the adult lung following left PNX is remodeling of the remaining alveolar structure without significant new tissue growth.

Section snippets

Critique of previous studies

There are several potential sources of error in these early results. First, the number of animals was small owing to the chronicity of the study; our major objective then was to develop the techniques for measuring lung function during exercise. The animals acted as their own controls for repeated physiologic studies over 5 years before and at different times following left PNX; therefore we did not have simultaneous control animals for comparison of morphometric results. Second, potential

Summary of findings

These recent studies confirm our earlier conclusion that compensation to left PNX in the adult animal does not involve a net growth of alveolar septal tissue in the remaining lung. The major ultrastructural responses include the following: (a) Capillary distention enlarges alveolar capillary volume as well as surface area leading to an enhanced diffusing capacity; the magnitude of enhancement estimated by morphometric and physiologic methods are similar. These results provide one anatomical

Relevance to exercise physiology

A reduced lung diffusing capacity is the main cause of arterial hypoxemia and exercise impairment in foxhounds after PNX (Hsia et al., 1990a, Hsia et al., 1990b, Hsia et al., 1991). The various compensatory mechanisms: alveolar microvascular recruitment, septal remodeling and tissue growth, serve the same end-point of enhancing diffusive oxygen transport. Microvascular recruitment occurs within minutes of left PNX and increases diffusing capacity of the remaining lung by unfolding gas exchange

Acknowledgement

This work was supported by National Institutes of Health grants R01 HL045716, HL040070, HL054060 and HL062873. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute or of the National Institutes of Health.

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