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Muscle wasting is commonly seen in patients with sepsis, severe injury, and cancer [, ]. The loss of muscle mass in these conditions mainly reflects ubiquitin-proteasome-dependent degradation of myofibrillar proteins although other proteolytic mechanisms may be involved as well []. Muscle atrophy is regulated by multiple factors, including glucocorticoids [], the pro-inflammatory cytokines, interleukin (IL)-1(3 and tumor necrosis factor (TNF)-α [, ], and myostatin []. In addition to these catabolic factors, a lack of anabolic signals, such as insulin-like growth factor (IGF)-1 and insulin, is probably also important for the development of muscle wasting in various catabolic conditions.

Multiorgan dysfunction is a major cause of mortality in the intensive care unit (ICU) []–[]. Sequential organ dysfunction syndrome was first described by Tilney et al. [] in 1973 in a cohort of 18 patients after repair of ruptured abdominal aortic aneurysm and renal failure. The terms multiple organ failure syndrome (MOFS), multiple organ system failure (MOSF), and multiple organ failure (MOF) have since been used to describe this syndrome []. Uncontrolled infections were initially thought to be the main cause of multiorgan dysfunction; however, massive activation of inflammatory mediators following other insults, such as severe trauma, may precipitate a similar condition. In 1992, the American College of Chest Physicians/Society of Critical Medicine (ACCP/SCCM) consensus conference [] recommended definitions of sepsis and the proposed systemic inflammatory response syndrome (SIRS). The term multiple organ dysfunction syndrome was also proposed to describe this syndrome; however, firm definitions of organ dysfunction were not established. Several scoring systems have subsequently been developed to quantify organ dysfunction in ICU patients.

The inflammatory response - induced and regulated by a variety of mediators such as cytokines, prostaglandins, and reactive oxygen species (ROS) - is the localized host’s response of the tissue to injury, irritation, or infection. In a very similar and stereotyped sequence, the mediators are thought to induce an acute phase response orchestrated by an array of substances produced locally or near the source or origin of the inflammatory response. Despite its basically protective function, the response can become inappropriate in intensity or duration damaging host tissues or interfering with normal metabolism. Thus, inflammation is the cause and/or consequence of a diversity of diseases and plays a major role in the development of remote organ failure. Better knowledge of the underlying mechanisms of these processes is, therefore, a fundamental pre-requisite fostering the molecular understanding of novel therapeutic targets or diagnostic variables.

Severe sepsis is a common cause of critical illness and death on the intensive care unit (ICU). It is estimated that severe sepsis accounts for more than 9% of all annual deaths in the United States, comparable to the figure for myocardial infarction. Interestingly, recent human studies suggested that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins, widely used in the treatment of hypercholesterolemia and atherosclerosis, have some protective effects in bacteremia, sepsis, and related problems, independent of their cholesterol-lowering effects []–[]. The growing body of evidence gives rise to the question of whether statins have a role in established sepsis as an adjuvant therapy, in the primary prevention of sepsis or both, and what the mechanisms of action are.

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by acute hypoxemic respiratory failure and bilateral pulmonary infiltrates that are not attributable to left atrial hypertension []. ALI/ARDS is a heterogeneous disease with a complex pathophysiology that may occur in response to a direct pulmonary or indirect systemic injury []. ALI and ARDS are different spectrums of the same condition. ALI is characterized by a PaO/FiO ratio of less than 300 mmHg (40 kPa). ARDS, the more severe end of the spectrum on the basis of oxygenation criteria, is defined by a PaO/FiO ratio of less than 200 mmHg (26 kPa). A recent prospective cohort study estimated the incidence of ALI to be 79/ 100,000 person years []. Mortality remains high although more recent trials have reported a lower mortality [, ].

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases belonging to the metzincin superfamily of metalloproteinases. MMPs can degrade most of the components of the extracellular matrix and basement membrane. In addition, these enzymes can cleave some inflammatory mediators. This variety of substrates gives MMPs a wide number of functions during physiologic and pathologic processes. In this sense, many of the MMPs are not expressed in normal tissues, but expression and activity increases dramatically during matrix turnover, inflammation and repair.

Acute lung injury (ALI), along with its most severe form acute respiratory distress syndrome (ARDS), is one of the most challenging conditions in critical care medicine. ARDS continues to have a mortality of more than 35 % despite improvements in ventilator strategies and management of sepsis []. Inflammation and increased vascular permeability are characteristics of ARDS. Vascular endothelial growth factor-A (VEGF-A) is a multi-functional cytokine known to play a pivotal role in angiogenesis and vascular permeability leading to interest in its potential role in ARDS. There is a body of work suggesting that VEGF plays a major role in lung development; however, it is expressed more highly in the healthy adult lung than any other organ suggesting a physiological role []. This apparent contradiction leads to controversy about the role of VEGF in ARDS.

The acute respiratory distress syndrome (ARDS) is a lethal inflammatory disorder of the lung. Its incidence is estimated at 75 cases per 100,000 population and appears to be increasing []. Even with optimal treatment, mortality is about 30% [–]. As such, ARDS represents a major public health problem. The effects of two recent crises created by unusual viral infections of the respiratory tract — the severe acute respiratory syndrome (SARS) epidemic caused by the novel SARS coronavirus [, ] and the bird flu [] highlight the importance of research into ARDS. Both viruses cause an ARDS-like picture. Because lung repair and regeneration contribute substantially to the pathophysiology of ARDS, understanding these processes is essential []. This chapter focuses on specific cell populations and markers involved in cell division and regeneration. In addition, a brief review of two pathways intimately associated with cell division is provided because of their potential for pharmacologic manipulation.

The extracellular matrix represents the three-dimensional scaffold of the alveolar wall, which is composed of a layer of epithelial and endothelial cells, their basement membrane, and a thin layer of interstitial space lying between the capillary endothelium and the alveolar epithelium []. In the segment where the epithelial and endothelial basement membranes are not fused, the interstitium is composed of cells, a macromolecular fibrous component, and the fluid phase of the extracellular matrix, functioning as a three dimensional mechanical scaffold characterized by a fibrous mesh consisting mainly of collagen types I and III, which provides tensile strength, and elastin conveying an elastic recoil [, ]. The three-dimensional fiber mesh is filled with other macromolecules, mainly glycosaminoglycans (GAGs), which are the major components of the non-fibrillar compartment of the interstitium []. In the lung, the extracellular matrix plays several roles, providing: a) mechanical tensile and compressive strength and elasticity; b) a low mechanical tissue compliance, thus contributing to the maintenance of normal interstitial fluid dynamics []; c) low resistive pathway for effective gas exchange []; d) control of cell behavior by binding of growth factors, chemokines, cytokines, and interaction with cell-surface receptors [].

Intubation of the trachea with a cuffed tube can be performed by the translaryngeal route (endotracheal tube) or through a tracheal stoma (tracheostomy tube). Tracheal intubation by one of these routes is the only way to simultaneously provide a secure airway, ventilatory support, and convenient access to the trachea. Unfortunately, the presence of an artificial airway bypasses many of the patient’s natural defenses and so increases the chances of upper and lower airway colonization, aspiration, and infection []. Sedatives, analgesics or muscle relaxants may be required to improve tolerance of the airway; this risks cardiovascular, respiratory and neuromuscular complications. It is, therefore, desirable to avoid the use of artificial airways, for example, by using facemask oxygen or an external airway interface to achieve non-invasive ventilation (NIV). Indeed it has become clear that NIV as opposed to tracheal intubation can reduce morbidity and mortality in the critically ill. When an artificial airway is required it is the responsibility of both the medical devices industry and the clinician to minimize the complications consequent to its use.