Pro: Most Climbers Develop Subclinical Pulmonary Interstitial Edema Annalisa Cogo 1 and Giuseppe Miserocchi 2 Introduction I nterstitial edema is the first appearance of water accu- mulation in the lung and has been reported to affect a large majority of otherwise healthy climbers during acute exposure to high altitude. In the following, we will review the hypoxia- induced changes of the main mechanisms implicated in the regulation of lung fluid homeostasis, the changes induced in lung physiology by interstitial fluid accumulation, and the diagnostic tools available to demonstrate the presence of in- terstitial edema at high altitude Control of Lung Interstitial Water Volume The air–blood barrier (ABB) hosts the capillary network whose surface area is *2000 cm 2 /g lung tissue. This incred- ibly high capillary surface area coupled to the extreme thin- ness of the ABB (0.2 to 0.3 mm) optimizes gas diffusion thanks to a functional setting that reduces to a minimum fluid fil- tration from capillaries to the interstitial space, as well as the volume of the extravascular water. The relative ‘‘dryness’’ of the lung interstitium is maintained by a subatmospheric in- terstitial pressure of *À10 cm H 2 O (Miserocchi et al., 1990) that results from the balance between a relatively low water and solute permeability in the microvascular district and a powerful draining action of lymphatics When conditions of increased microvascular filtration are established, the lung, at variance with other organs, strongly resists the development of edema, thanks to several mechanisms that cooperate to keep at a minimum the volume of the extravascular fluid, and only allows its minimal increase ( Miserocchi, 2009). A key role in buffering the increase in extravascular water is played by proteoglycans (PG) in two ways (Miserocchi et al., 2001a). These molecules are highly hydrophilic and therefore can bind excess interstitial water through their glycosaminogly- can chains, forming gellike structures whose steric hindrance allows the control of the permeability of the pores of the basement membrane and of the channels within the intersti- tial matrix where water circulates. The other important role played by proteoglycans reflects their macromolecular as- sembly as link proteins, assuring low tissue compliance. This mechanical feature represents the main line of defense against the development of edema. In fact, a minor increase in ex- travascular water volume (in the range of 10% of resting value) results in a remarkable increase in interstitial pressure (from *À10 up to *5 cm H 2 O), which, in turn, counteracts further microvascular fluid filtration (the‘‘tissue safety factor’’ against edema development) (Miserocchi et al., 2001a) This condition has been identified as interstitial lung edema and ought to be regarded as the main mechanism protecting the lung against the development of severe edema. The volume of the lung interstitial compartment is so strictly controlled that it is difficult to detect initial deviations from the physiological state; in practice, a great advantage in the physiological set- ting turns to be a disadvantage on a clinical basis because it prevents an early diagnosis of developing disease (Mis- erocchi, 2009). In this regard, it is noteworthy to recall that in an experi- mental model of lung edema in rats, it was shown that reac- tance measured at low frequency (4 to 5 Hz) (an index reflecting the elastic properties of the tissues or the resistance of distal airways) decreased progressively and significantly with time when interstitial edema was developing, while water accumulation in the interstitial compartment was maintained steady within 10% of control value (Dellaca ` et al., 2008). Therefore, it was concluded that monitoring of reac- tance could have a potential use in clinical practice as an early marker of developing edema, before any change in lung compliance or alveolar fluid accumulation occurs. Hypoxia Exposure in Experimental Animals In an animal model, 12% oxygen exposure, roughly corre- sponding to 4300 m, lowered arterial Po 2 and Pco 2 down to 1 Centro Studi Biomedici Applicati allo Sport, Universita ` di Ferrara, Italy. 2 Dipartimento di Medicina Sperimentale, Universita ` di Milano Bicocca, Italy. HIGH ALTITUDE MEDICINE & BIOLOGY Volume 12, Number 2, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089/ham.2011.0004 121